SK33299A3 - Tricyclic compounds useful for inhibition of farnesyl protein transferase - Google Patents

Abstract

Novel compounds of formula (1.0) are disclosed. Compounds of formula (1.0) are represented by the compounds of formula (1.4) or (1.5) wherein R<1>, R<3> and R<4> are each independently selected from halo. Also disclosed are methods of inhibiting farnesyl protein transferase and the growth of abnormal cells, such as tumor cells.

Description

Technical field

WO95 / 10516 published April 20, 1995 discloses the discovery of tricyclic compounds useful for inhibiting farnesyl protein transferase.

Given the current interest in farnesyl protein transferase inhibitors, a welcome contribution of a compound useful for inhibiting farnesyl protein transferase would be a welcome contribution. Such a contribution is provided by the present invention.

The state of the art

The present invention provides compounds useful for inhibiting farnesyl protein transferase (FPT). The compounds of the invention have the following formula:

or a pharmacologically acceptable salt or solvate thereof, wherein one of the atoms a, b, c and d is N or NR ⁹ , wherein R ⁹ is O ', -CH ₃ or - (CH ₂ ) _n CO ₂ H when n is 1-3, and the remaining groups a, b, c, d are CR ¹ or CR ² ; or wherein each of a, b, c and d is independently selected from CR ¹ or CR ² ;

each R ¹ and each R ² is independently selected from: H ·, halogen, -CF3, ^-OR10 (e.g. -OCH 3), -COR ^lu, -SR ¹⁰ (e.g., -SCH 3 and -SCH2C6H5), -S ( O) t R ⁿ (wherein t is 0, 1 or 2, e.g. -SOCH 3 a

-SO ₂ CH _3), -SCN, -N (R ¹⁰⁾ 2, -NR ¹⁰ R ^n, -N02, -OC (O) R ^10, -CO 2 R ^10,

-OCO ₂ R ^n, CN * NHC (O) R ^10, -NHSO 2 R ^10, -CONHR ^10, -CONHCH2CH ₂ OH, -NR ¹⁰ COOR ^n,

-SR ⁿ C (O) OR ¹¹ (e.g. -SCH 2 CO 2 CH 3), -SR ⁿ N (R ⁷⁵ ) 2, wherein each R ⁷⁵ is independently selected from: H and -C (O) OR ¹¹ (e.g. -S (CH 2) 2 NHC (O) t -Butyl and -S (CH 2) 2 NH 2), benzotriazol-1-yloxy, tetrazol-5-ylthio, or substituted tetrazol-5-ylthio (e.g., alkyl substituted tetrazol-5-ylthio such as 1-methyltetrazol-5-ylthio), alkynyl, alkenyl or alkyl, wherein said alkyl or alkenyl group may be preferably substituted with halogen, -OR ¹⁰ or -CO ² R ¹⁰ ;

R ³ and R ⁴ are the same or different and each independently represents H, which of each of R ¹ and R ² or R ³ and R ⁴ together represent a saturated or unsaturated C 5 -C 7 ring attached to the benzene ring (Ring III);

R ⁵ , R ⁶ , R ⁷ and R ⁸ are independently H, -CF 3 -COR ¹⁰ , alkyl or aryl, wherein said alkyl or aryl is preferably substituted with -OR ¹⁰ , -SR ¹⁰ , -SfOKR ¹¹ , -N (R ¹⁰ ) COOR ¹¹ , -N (R ¹⁰ ) 2,

-N0 _2, -COR ^10, -OCOR ^{10, in} -OCO2R, -CO 2 R ^10, OPO ₃ R ^10, or R ⁵ in combination with R ⁶ to represent = 0 or = S and / or ^R7 with ^R8 is = O or = S;

R ¹⁰ represents H, alkyl, aryl or aralkyl (e.g. benzyl);

R ¹¹ represents alkyl or aryl;

X represents N, CH or C, wherein C may suitably have a double bond (represented by the dotted line) with carbon atom 11;

the dotted line between carbon atoms 5 and 6 is preferably a double bond, so that in the presence of the double bond A and B are independently -R ¹⁰ , halogen, -OR ¹¹ , -OCO ² R ¹¹ , or -OC (O) R ¹⁰ , and in the absence of a double the bonds between carbon atoms 5 and 6, A and B are independently H ₂ ;

- (OR ¹¹ ) 2; H and halogen, dihalogen, alkyl and H, (alkyl) 2, -H and -OC (O) R ¹⁰ , H and -OR ¹⁰ , = O, aryl and H, = NOR ¹⁰ or -O- (CH 2) _p -O-, wherein p is 2, 3 or 4; and

W represents a group selected from the following groups:

(D (2)

O H II I

-CC - (CH 2 -N 'R ¹²

O H II I — C — C — N

Cy _{2) a)} (3) (4)

The 11 -CC- (CII _{2) of} R ¹⁵ s J?

À »2 _and -C _{(CH2) z} -CR 'wherein: ^Λ

R ¹² is selected from the group consisting of: a) H; b) alkyl c) aralkyl (e.g. benzyl); ad) heteroarylalkyl (heteroaralkyl) (e.g., -CH ₂ -imidazole);

R ¹³ and R ¹⁴ are each independently selected from the group consisting of: a) H; b) -C (O) OR ¹⁶ wherein R ¹⁶ represents alkyl, aralkyl and heteroaralkyl; c) -SO 2 R ¹⁷ , wherein R ¹⁷ is selected from the group consisting of -NH 2, -N (alkyl) ₂ , wherein each alkyl is the same or different (e.g. -N (CH ₃ ) 2), alkyl (e.g. C _1-6) alkyl such as methyl), aryl, aralkyl, heteroaryl and heteroaralkyl; d) -C (O) R ¹⁸ , wherein R ¹⁸ is selected from the group consisting of aryl (e.g., phenyl), alkyl, aralkyl, heteroaryl and heteroaralkyl; e) C 1-6 alkyl; f) alkaryl; g) C ₃ _ ₆ cycloalkyl;

r is 0, 1 or 2;

s is 1, 2, 3, 4, or 5 (preferably 3 or 4), and each Y for each -CY ₂ group is independently selected from H or

-OH, provided that both Y substituents of each -CY ₂ group are not -OH, and provided that for the -CY ₂ group at the alpha position relative to the nitrogen, both Y substituents are H, preferably each Y is H, - CH ₂ - group, so the group so each -CY ₂ group is

O H

II I »'R CCN f)' (CY ₂ ) p

O H

II I .R - C - C - N

(CH ₂ )) forms a 3-, 4-, 5-, 6- or 7- (preferably 5- or 6-) membered ring (e.g. piperidil or pyrrolidinyl);

v is 0, 1 or 2;

R ¹⁵ is selected from the group consisting of:

a) heteroaryl (e.g. imidazolyl);

(b) groups selected from:

(1) —O-N = C '

CH,

OAc

ABOUT

II

CH, (2) - .alpha.-oc ₂ h ₅ HH ₂

H

(3) -O-N

5) -CH (OCH ₂ CH ₃ ) ₂

6) -OH, and

7) -CN; and (c) a heterocycloalkyl selected from the group consisting of:

z is 0, 1, 2, 3, 4, or 5, wherein each -CH ₂ - group is preferably substituted with an -OH group, i.e. each H in each -CH 2 'group can be preferably replaced by -OH and the preferred substitution of each -CH ₂ - group does not depend on the substitution of any other -CH ₂ - group, generally, each -CH ₂ - group is not substituted;

R ²² represents a group selected from:

5) alkyl (e.g. -CH ₃ ),

6) -OR ²³ , wherein R ²³ is selected from the group consisting of: alkyl, aryl and H, and ^71- N 'R ^{25 25} are independently selected from the group consisting of: (e.g., -OCH ₃ ), -OH, -CH ₂ CO ₂ H, -OCH ₂ Ph (i.e.

where R ² * and R -NH ₂ , alkoxy -OCH ₂ C ₆ H ₅ ), -CH (OCH ₃ ) CH (CH ₃ ) ₂

HoC-CH alkyl, aryl, H, aralkyl and heteroaralkyl; or R ²⁴ and R ²⁵ together form a carbon chain with 4 or 5 (-CH ₂ -) groups such that R ²⁴ and R ²⁵ together with the nitrogen to which they are attached form a 5- or 6-membered heterocycloalkyl ring.

The compounds of the invention: i) significantly inhibit farnesyl protein transferase in vitro, but not geranylgeranyl protein transferase 1; ii) block a phenotypic change induced by a form of transformed Ras which is a farnesyl acceptor but not a form of transforming Ras prepared as a geranylgeranyl acceptor; iii) block intracellular processing of Ras, which is a farnesyl acceptor but not

Ras prepared as a geranylgeranyl acceptor; and iv) block abnormal cell growth in the culture induced by the transforming Ras.

The compounds of this invention inhibit farnesyl protein transferase and farnesylation of the oncogenic Ras protein. The invention further provides a method of inhibiting farnesyl protein transferase (e.g., ras farnesyl protein transferase) in a mammal, particularly a human, by administering an effective amount of the tricyclic compounds described above. Administration of the compounds of this invention to patients to inhibit farnesyl protein transferase is a suitable treatment for the tumors described below.

The present invention provides a method of inhibiting or treating abnormal cell growth, including transformed cells, by administering an effective amount of a compound of the invention. Abnormal cell growth means growth independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This includes growth of: 1) tumor cells (tumors) expressing an activated Ras oncogene; 2) tumor cells in which the Ras protein is activated as a result of an oncogenic mutation in another gene; and 3) benign and malignant cells of other proliferative diseases in which abnormal Ras activation occurs.

The present invention also provides a method of inhibiting or treating tumor growth by administering to a mammal (e.g., a human) in need of such treatment an effective amount of the tricyclic compounds described herein. The present invention provides a method of inhibiting or treating the growth of tumors expressing an activated Ras oncogene by administering an effective amount of the compounds described above. Examples of tumors that can be inhibited or treated and are not limited by this include: lung cancer (e.g., lung adenocarcinoma), pancreatic cancer (e.g., pancreatic cancer such as exocrine pancreatic cancer), colon cancer (e.g., colorectal cancer) such as adenocarcinoma and colon adenoma), myeloid leukemia (e.g., acute myeloid leukemia (AML)), thyroid follicular cancer, myelodysplastic syndrome (MDS), bladder cancer, epidermal cancer, and breast cancer.

It is envisaged that the present invention also provides a method of inhibiting and treating proliferative diseases, both benign and malignant, in which Ras proteins are aberrantly activated as a result of an oncogenic mutation in other genes - i.e. The ras gene itself is not activated by mutation into an oncogenic form - wherein said inhibition or treatment is achieved by administering an effective amount of the tricyclic compounds described herein to a mammal (e.g., a human) in need of such treatment. For example, a benign proliferative disorder neurofibromatosis or tumors in which Ras is activated due to mutation or over-expression of tyrosine kinase oncogenes (e.g. neu, src, abl, lck, and fyn) may be inhibited or treated with the tricyclic compounds described herein.

Tricyclic compounds useful in the methods of the invention inhibit or treat abnormal cell growth. Without wishing to be bound by theory, it is believed that these compounds may act by inhibiting G-protein function, such as e.g. ras p21, by blocking the isoprenylation of the G protein, making them suitable for the treatment of proliferative diseases such as tumor growth and cancer. Without wishing to be bound by theory, it is believed that these compounds inhibit ras farnesyl protein transferase and thus exhibit antiproliferative activity against transformed cells.

SUMMARY OF THE INVENTION

The following terms are further used as defined below unless otherwise indicated.

Ac - represents acetyl;

MH ⁺ - represents the molecular ion plus the hydrogen of the molecule in the mass spectrum;

M ⁺ - represents the molecular ion of the molecule in the mass spectrum;

Benzotriazol-1-yloxy represents

O-1-Methylterazol-5-ylthio represents N-N

CH ₃

Alkenyl represents a straight branched carbon chain having at least one carbon-carbon double bond of 2 to 12 carbon atoms, preferably 2 to 6 carbon atoms, and most preferably 3 to 6 carbon atoms;

Alkynyl- represents a straight branched carbon chain having at least one triple bond between carbon atoms containing 2 to 12 carbon atoms, preferably 2 to 6 carbon atoms;

Alkyl- (including the alkyl moiety of aralkyl and heteroarylalkyl) - represents a straight branched carbon chain of 1 to 20 carbon atoms, preferably 1 to 6 carbon atoms;

Aralkyl- represents an aryl group as defined below, bound to an alkyl group as defined above, the alkyl group preferably being -CH ₂ -, (e.g. benzyl);

Aryl- (including the aryl moiety of aralkyl and arylalkyl) represents a carbocyclic group of 6 to 15 carbon atoms with at least one aromatic ring (e.g., aryl is a phenyl ring), wherein all available carbocyclic group carbon atoms suitable for substitution are considered as possible coupling points said carbocyclic group may preferably be substituted (e.g., 1 to 3) with one or more halogen atoms, alkyls, hydroxy, alkoxy, phenoxy, CF ₃ , amino, alkylamino, dialkylamino, -COOR ¹⁰ , or -NO 2;

I

BOC- represents -C (O) OC (CH ₃ ) ₃ ;

-CH ₂ -imidazolyl represents an imidazolyl group bound by any substitutable carbon on the imidazole ring with -CH ₂ -, thus:

H

such as -CH ₂ - (2-, 4-, or 5-) imidazolyl, for example

Et - represents ethyl;

Halogen- represents fluorine, chlorine, bromine and iodine; Heteroaryl- represents cyclic groups, preferably substituted with R ³ and R ⁴ , phenyl or CH ₂ C (O) OCH ₃ , said cyclic groups having at least one heteroatom selected from O, S or N; said heteroatom disrupts the carbocyclic ring structure and has a sufficient number of π-electrons to maintain the aromatic character; the aromatic heterocyclic group preferably contains 2 to 14 carbon atoms e.g. (2-, 4 or 5) imidazolyl, triazolyl,

2-, 3- or 4-pyridyl or pyridyl N-oxide (preferably substituted with R ³ and R ⁴ ), wherein the pyridyl N-oxide may be depicted as:

Heteroarylalkyl (heteroaralkyl) - represents a heteroaryl group as defined above, attached to an alkyl group as defined above, and preferably is -CH ₂ -, (e.g., -CH ₂ - (4- or 5-) imidazolyl);

Heterocycloalkyl- represents a saturated, branched or t

unbranched carbocyclic ring of 3 to 5 carbon atoms, preferably 4 to 6 carbon atoms, in which the carbocyclic ring is interrupted by 1 to 3 hetero groups selected from -O-, -S- or -NR ¹⁰ ; suitable heterocycloalkyl groups include: 1) 2- or 3-tetrahydrofuranyl, 2) 2- or 3-tetrahydrothienyl), 3) 2-, 3- or 4-piperidinyl, 4) 2- or 3-pyrrolidinyl, 5) 2- or 3-piperazinyl; and 6) 2- or 4-dioxanyl;

Ph- represents phenyl

The following solvents and reagents are abbreviated herein: tetrahydrofuran (THF); isopropanol (iPrOH); ethanol (EtOH); methanol (MeOH); acetic acid (HOAc or AcOH); ethyl acetate (EtQAc); N, N-dimethyl forms d (DMF); trifluoroacetic acid (TFA) and trifluoroacetic anhydride (TFAA); 1-hydroxybenzotriazole (HOBT); 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (DEC); diisobutylaluminum hydride (DIBAL); and 4-methylmorpholine (NMM).

The numbering of the substituents R ¹ , R ² , R ³ and R * is based on the following numbering of the ring structure:

Compounds of formula 1.0 include those wherein the lower piperidinyl group is a 4- or 3-piperidinyl group, i.e.:

Compounds of formula 1.0 include compounds wherein R ² and R ⁴ are H and R ¹ and R ³ are halogen atoms (preferably independently selected from Br or Cl). E.g. R ¹ is Br and R ³ is Cl. These compounds include those wherein R ¹ is at the 3-position and R ³ is at the 8-position, e.g. 3-Br and 8-C1. Compounds of formula 1.0 also include compounds wherein R ² is H and R ¹ , R ³ and R ⁴ are halogen atoms (preferably independently selected from Br or Cl).

Preferably, compounds of Formula 1.0 are represented by a compound of Formula 1.1:

wherein all substituents are defined as in Formula 1.0.

Preferably R ² is H and R ¹ , R ³ and R ⁴ are halogen atoms; a is N and b, c and d are carbon atoms; A and B are both H ₂ ; a preferred bond between C5 and C6 is absent; X is CH and R ⁵ , R ⁶ , R ⁷ and R ⁸ are H. More preferably, R ¹ , R ³ and R ^{4 are} independently selected from Br or Cl. Most preferably R ¹ is Br R ³ and R ⁴ are independently selected from a pair of Cl or Br.

More preferably, compounds of Formula 1.0 are represented by compounds

preferably Br or Cl; and A, B, X and W are defined as in Formula 1.0. More preferably, both A and B are each H ₂ ; a preferred bond between C5 and C6 is absent; and X is CH. Most preferably R ¹ is Br; R ³ and R ⁴ are independently selected from a pair of Br or Cl, and more preferably R ³ is Cl and R ⁴ is Br; A and B are each H ₂ ; a preferred bond between C5 and C6 is absent; X is CH; and R ⁵ , R ⁶ , R ⁷ and R ⁸ are H.

Examples of R ¹⁵ include:

Γ ^? O 1 ^ ° ° »ΓΥ

13 Η η13

II I, ^{R =} CC-ICH2 -N,

R ^{12 R} where W represents:

ar is 0: 1) preferably R ^{12 is} selected from the group consisting of: a) H; b) alkyl; c) aralkyl; ad) heteroaralkyl; and most preferably R ^{12 is} selected from the group consisting of: a) H, b) methyl, c) -CH 2 -imidazole and d) benzyl; 2) preferably R ¹³ and R ^{14 are} independently selected from the group consisting of: a) H; b) -C (O) OR ¹⁶ wherein R ¹⁶ is alkyl; c) -SO 2 R ¹⁷ wherein R ¹⁷ is alkyl or aryl; d) -C (O) R ¹⁸ ; wherein R ¹⁸ is aryl; ae) alkyl; and most preferably R ¹³ and R ¹⁴ are independently selected from the group consisting of: a) H, b) -C (O) OC (CH 3) 3, c) -SO 2 CH 3 and d) -C (O) -phenyl. It is preferred that R ¹³ or R ¹⁴ is -C (O) OR ¹⁶ , -SO 2 R ¹⁷ , -C (O) R ¹⁸ , alkaryl or cycloalkyl, the remainder of R ¹³ or R ¹⁴ being H. A preferred combination of substituent groups comprises: 1 R ¹² is alkyl (more preferably methyl), R ¹³ is -C (O) OR ¹⁶ (more preferably -C (O) OC (CH 3) 3) and R ¹⁴ is H; 2) R ¹² is heteroarylalkyl (more preferably -CH 2 - (4 or 5) -imidazolyl), R ¹³ is H or -C (O) OR ¹⁶ (more preferably H or -C (O) OC (CH ₃ ) ₃ ) and R ¹⁴ is H; 3) R ¹² is aralkyl (more preferably benzyl), R ¹³ is

-C (O) OR ¹⁶ (more preferably -C (O) OC (CH 3) 3) and R ¹⁴ is H; 4) R ¹² is Ή, R ¹³ is -C (O) OR ¹⁶ (more preferably -C (O) OC (CH 3) ₃ ) and R ¹⁴ is H; 5) R ¹² is H, R ¹³ is -SO 2 R ¹⁷ (more preferably -SO ₂ CH ₃ ) and R ¹⁴ is H; and 6) R ¹² is H, R ¹³ is -C (O) R ¹⁸ (more preferably -C (O) -phenyl) and R ¹⁴ is H.

Those skilled in the art will appreciate that the W substituent described in the preceding paragraph can be derived from known amino acids with one carboxyl group and one amino group. Examples of such amino acids are (but are not limited to) glycine, alanine, phenylalanine, asparagine, and histidine. For example, Morrison and Boyd, Organic Chemistry, Fifth Edition, Allyn and Bacon, Inc., Boston, p. 1346-1347. The disclosure is incorporated herein by reference.

When W is oh _n i3

II, ^{R -} c - (CH 2) _n -N

R> ^Rh and ² is 1 or 2, preferably R ¹² is H, and R ¹³ and R ¹⁴ are independently selected from alkyl, most preferably R ¹³ and R ¹⁴ the same alkyl group (e.g. methyl).

When W is: o H

II I R —C-C-N

O H 'n

II IR ¹³

-C-C-N f preferably f

MCY ₂ ) / (CH 3 / s is preferably 3 so that a pyrrolidone ring is formed and R ¹³ is preferably H or -C (O) OR ¹⁶ where R ¹⁶ is alkyl; most preferably R ¹³ is H or -C (O , OC (CH _{3) third}

When W is: _{o H} ^{11 1} .C - C - (CH ₂ ) $ - R ¹⁵

Av ¹² av is O, preferably R ¹² represents H and R ¹⁵ represents heteroaryl or heterocycloalkyl. Most preferably, R ^{1 S} is heteroaryl said heteroaryl is imidazolyl and when ^R15 is heterocycloalkyl said heterocycloalkyl is

When W is:

OH ¹¹ '—CCH ₂ ) - R ¹⁵

Ŕ ¹² av is 1 or 2, preferably R ¹² is H and R ¹⁵ is heterocycloalkyl. Most preferably, R ¹² is H and R ¹⁵ is heterocycloalkyl, e.g.

ABOUT

When W is:

0 ° -C-1CHak-CR ²² and z is 0, R ²² preferably represents ¹ R ²⁴

Z —N 'R ²⁵ and R ²⁴ and R ²⁵ preferably represent H.

When W represents:

ABOUT

II

ABOUT

II - C - (CH 2 - CR ^{22 a)} is 1, 2, 3, 4 or 5, R ²² preferably represents -OR ²³ and R ²³ preferably represents alkyl and most preferably methyl.

*

Preference is given to compounds of formulas 1.2A and 1.3A:

when X is CH or N, and R ¹ , R ³ and R ⁴ are halogen atoms.

Preferred compounds of the invention are those of the following formulas:

are as defined above, wherein the compounds of Formula 1.5A are more preferred.

Those skilled in the art will appreciate that the W substituent:

OH II wherein r is 0, comprising CC- _{(CH2) r} - \ .14 »\ £ - ^{R 13} \ Λ to, ^N X

R ¹ 'H,' ^R ' ³ ' Λ N f ^N X R ' ⁴

HR ¹² and W substituent:

OH ^{11 1} IR

-CC- (CH ₂₎ v R ¹⁵

Ŕ ¹² where v is 0, includes

Representative compounds of formula 1.0 wherein W is R ¹³

O H II I -C-C- (CH 2 -N '> 12 and r is O, include:

ABOUT

br

Cl (10.0)

Representative compounds of formula 1.0 wherein W is OH ¹¹ 'is -CC- (CH ₂ R ¹⁵⁾

R ¹² av is 0, include:

Ph = phenyl

Representative compounds of formula 1.0 wherein W is

Compounds of formula 1.0 wherein W is OO-C-1CHaJf-CR ²² az is 0 include:

(59.0-Β)

H ι

N CO ₂ H

(104.0-Β) .OCH

Ο

Ο

Compounds of formula 1.0 wherein W is o

II II - C - CH 2 - C - R 22 and z is 1, 2, 3, 4 or 5 include:

(67.0-Β)

ΝΗ.

br

Compounds according to

ABOUT

or a pharmaceutically acceptable salt or solvate thereof.

The compounds of this invention also include 1-N-oxides,

i.e. compounds of formula:

wherein ολλ / vv is the remainder of the compound, or a pharmaceutically acceptable salt or solvate thereof.

The optical activity of ((+) or (-)) is measured in methanol or ethanol at 25 ° C.

The present invention also encompasses the above compounds in an amorphous or crystalline state.

The lines drawn in the aromatic ring mean that the labeled moiety can be attached to any of the substitutable carbon atoms in the ring.

Some of the compounds of this invention may be in various isomeric forms (e.g., as enantiomers or diastereoisomers) including atropisomers (i.e., compounds wherein the 7-membered ring is in a rigid conformation such that the carbon atom 11 is in the over- or under-position. fused benzene rings due to the presence of the Br substituent at position 10). The invention contemplates the existence of all such isomers both in pure form and as a mixture, including a racemic mixture. Enolforms are also envisaged.

Some tricyclic compounds are naturally acidic, e.g. those having a carboxyl or phenol hydroxyl group. These compounds form pharmaceutically acceptable salts. Examples of such salts include sodium, potassium, calcium, aluminum, gold, silver and lithium salts. For example, compounds with the -OR ²³ group where R ²³ is H may form sodium or lithium salts - i. with -ONa or -OLi group. Also contemplated are salts formed with pharmaceutically acceptable amines such as ammonium, alkylamines, hydroxyalkylamines, N-methylglucamine and the like.

Some basic tricyclic compounds also form pharmaceutically acceptable salts, e.g. acid addition salts. For example, pyrido-nitrogen atoms form salts with a strong acid, they add compounds with basic substituents such as amino groups, and also form salts with weaker acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those skilled in the art. These salts are prepared by mixing the free base with a sufficient amount of the desired acid to form the salt in the usual manner. The free base form can be regenerated by treating the salt with a suitable dilute base solution, such as e.g. dilute aqueous solution of NaOH, potassium carbonate, ammonium carbonate and sodium. The free base forms differ from their salts by certain physical properties, such as solubility in polar solvents, but for purposes of the invention, the acid and base salts are equivalent to their respective free base forms.

All such acid and base salts are considered within the scope of the invention to be pharmaceutically acceptable salts, and for the purposes of the present invention, all acid and base salts are considered equivalent to the free forms of the respective compounds.

The compounds of the invention can be prepared according to the procedures described in WO95 / 10516 published April 20, 1995, in patent application no. No. 08 / 410,187, filed Mar. 24, 1995; No. 08 / 577,951, filed Dec. 22, 1995 (now unpublished); No. 08 / 615,760, filed March 13, 1996 (now unpublished), WO 97/23478 published July 3, 1997, which discloses the subject matter of patent application no. No. 08 / 577,951 and 08 / 615,760, in patent application no. No. 08 / 710,225, filed Sep. 13, 1996, and U.S. Pat. 08 / 877,453, filed June 17, 1997; the objects described herein are incorporated herein by reference; and following the procedures described below.

The compounds of the invention may be prepared

and

H wherein all substituents are as defined for Formula 1.0 with an appropriately protected piperidinyl acetic acid (e.g., 1-Nt-butoxycarbonylpiperidinyl acetic acid) together with DEC / HOBT / NMM in DMF for 18 hours at 25 ° C to give a compound of formula :

The compound of formula 21.0 is then reacted with either TFA or 10% sulfuric acid in dioxane and methanol, then with NaOH to form

can be prepared by reacting a compound of Formula 19.0 with 1-N-t-butoxycarbonylpiperidinyl-4-acetic acid as described above.

For example, compounds of Formula 22.0 include compounds of:

The preparation of these compounds is described in Examples 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, and 13, respectively.

The compounds of this invention can be prepared by reacting a compound of the formula:

H with the appropriate protected piperidinyl acetic acid (1-N-t-bptoxycarbonylpiperidinyl acetic acid) with DEC / HOBT / NMM in DMF for 18 hours at 25 ° C for compounds of formula:

(Eg.

together formation

The compound of formula 21.1 is then reacted with either TFA or 10% sulfuric acid in dioxane and methanol followed by addition of NaOH to give the compound of formula 22.1:

(22.1)

H

Anode formula 1.7

can be prepared by reacting a compound of formula 22.1 with an appropriate carboxylic acid in the presence of a condensing agent such as e.g. DEC and HOBT in dimethylformamide. The compound of formula 22.1 can optionally be reacted with an acid chloride or anhydride in a solvent such as e.g. pyridine.

The W group in Formula 1.7 may contain functionality that can be changed to other functionality by methods such as hydrolysis, which are well known in the art. For example, a compound of Formula 16.0-B can be converted to a compound of Formula 74-B, and a compound of Formula 35.0-B to a compound of Formula 52.0-B by treatment with methanolic potassium hydroxide followed by treatment with an acid. Likewise, compounds of Formula 86.0-B and 89.0-B can be converted to the corresponding compounds of Formula 88.0-B and 90.0-B by treatment with acids such as trifluoroacetic acid or dioxane saturated with HCl gas.

Compounds with 1-N-O group:

./ww* can be prepared from the appropriate pyridyl compounds:

Oxidation with m-chloroperoxybenzoic acid. This reaction is carried out in a suitable organic solvent, e.g. dichloromethane (usually anhydrous) or methylene chloride, at a suitable temperature, to provide compounds of the invention having an N-O substituent at the 1-position of Ring 1 of the tricyclic ring system.

Generally, a solution of the starting tricyclic compound in an organic solvent is cooled to 0 ° C before the addition of m-chloroperoxybenzoic acid. The reaction is then allowed to warm to room temperature over the reaction time. The desired product can then be separated using standard separation procedures. For example, the reaction mixture may be washed with an aqueous solution of a suitable base e.g. saturated sodium carbonate solution or NaOH (e.g. 1 N NaOH) and then dried over anhydrous magnesium sulfate. The solution containing the product can be concentrated in vacuo. The product can be purified by standard procedures e.g. silica gel chromatography (e.g. flash column chromatography).

Compounds N-O may optionally be prepared from intermediate:

using the above oxidation process with m-chloroperoxybenzoic acid and

wherein Q is a protecting group, e.g. BOC. After oxidation, the protecting group is removed by known methods. The N-O intermediate is then reacted to form the compounds of this invention.

Compounds of Formula 19.0 include compounds of Formula 19.1:

H

The compound of formula 19.1 is prepared by methods known in the art, e.g. by methods disclosed in WO 95/10561, U.S. Pat. No. 5,151,423 and in the other applications described below. The above intermediate can also be prepared by a process with the following steps:

(a) reacting the amide of the formula:

wherein R ¹¹ 'is Br, R ⁵ ' is hydrogen and R ⁶ 'is C 1 -C 6 alkyl, aryl or heteroaryl; R ⁵ is C 1 -C 6 alkyl, aryl or heteroaryl and R ⁶ 'is hydrogen; R ⁵ 'and R ⁶ ' are independently selected from the group consisting of C 1 -C 6 alkyl and aryl; or R ⁵ "and R ⁶ ", together with the nitrogen to which they are attached, form a ring of 4 to 6 carbon atoms or 3 to 5 carbon atoms and one heterogeneous molecule selected from the group consisting of -O- and NR ⁹ "-, wherein R ⁹ 'is H, C 1 -C ₆ alkyl or phenyl;

with a compound of formula

R ²³

R ³³ wherein R ^1a , R ^2a , R ^3a and R ^4a are independently selected from the group consisting of hydrogen and halogen and R ^1a is Cl or Br, in the presence of a strong base to give a compound of formula r ' ^b

R ²³

R ³³

b) reacting the compound of step a) with

i) POCl 3 to form a cyano compound of formula

ii) DIBALH to form an aldehyde of formula

R ²³

R ³³

c) reacting a cyano compound or an aldehyde with a piperidine derivative of the formula ^{M 9 L} wherein L is a leaving group selected from the group consisting of Cl and Br to form the corresponding ketone or alcohol below

I

d) i) cyclizing the ketone with CF 3 SO 3 H to give a compound of formula 13.0a, wherein the dotted line represents a double bond; or (ii) cyclizing the alcohol with polyphosphoric acid to form an intermediate wherein the dotted line represents a single bond.

A process for the preparation of intermediates disclosed in WO 95/10516, U.S. Pat. No. 5,151,423 and described below uses a tricyclic ketone intermediate. Such intermediates have the formula

R ^{1, b}

where R 11b, 1a

R ^2a , and R ⁴ "are independently selected from the group consisting of hydrogen and halogen, which may be prepared as follows:

a) reaction of a compound of the formula > Ub

QLW

XX

N 'Br

(i) an amine of the formula NHR ^{5a and} R ^6a , wherein R ⁵ and R ⁶ 'are as defined in the method described above, in the presence of a palladium catalyst and CO to form an amide of formula 11b

XX

NR ⁶³ R ii) with an alcohol of formula R OH ^1OA, wherein R ¹⁰ is nižšj. C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl, in the presence of a palladium catalyst and CO, to form an ester of the formula

OR ^{, 0a} followed by reaction of the ester with an amine of formula NH ^{R 5} and R ⁶ 'to form the amide;

b) reacting the amide with an iodine substituted benzyl compound

wherein R ¹ ', R ² ', R ^{3 and} R * ^a and R ^a are the same as above, in the presence of a strong base to give a compound of formula

R ' ^e 1τ 1 Γ rií ^ R ² " U J \ / M ^to R3a J = H NR ⁶ R ^{»r 4>} c) by cyclization compound from step b) with the reagent of formula R ^8a MgL, where R ⁸ 'is C 1 -C 6 alkyl, aryl or heteroaryl; and

L is Br or Cl, provided preferential cyclization of the compound wherein R ^5a or R ⁶ 'is hydrogen by reaction with a suitable protecting group.

The (+) - isomers of the compound of Formula 19.2

can be prepared with high enantioselectivity using the enzymatic transesterification method. Preferably the racemic compound of formula 19.3

reacts with an enzyme such as Toyobo LIP-300 and an acylating agent such as e.g. trifluoroethyl isobutyrate; the resulting (+) - amide is then isolated from the (-) - enantiomeric amine by procedures known in the art, and then the (+) - amide is hydrolyzed e.g. acid reflux such as e.g. H ₂ SO <and the resulting compound is reduced with DIBAL stream using techniques known in the art to obtain the corresponding optically enriched (+) - isomer of Formula 19.2 The racemic compound of formula 19.3 is optionally first reduced to the corresponding racemic compound of formula 19.2 and then exposed to an enzyme (Toyobo LIP-300) and an acylating agent as described above to form a (+) - amide which is hydrolyzed to form an optically active compound. (+) isomer.

Those skilled in the art will recognize that compounds of Formula 1.0 having other R ¹ , R ² , R ^3, and R * substituents can be prepared using the above enzymatic method.

For the preparation of compounds of formula 1.0 wherein W is

5? IN

-CC-, Cl _-- N

R ¹² r is 0, R ¹³ and R ¹⁴ are selected from H or -C (O) OR ¹⁶ , the compounds of Formula 20.0 or 22.0 are reacted with the appropriate protecting amino acids:

I? ´RHO — C-C-N '

Ŕ12 BOC in the presence of DEC and HOBt in dimethylformamide to give the corresponding compound of formula:

Reaction of compounds of Formula 23.0 or 24.0 with TEA in methylene chloride results in the corresponding deprotected compounds:

Compounds of formula 1.0 wherein

OH II I, -CC- _(CH2 R L _R ¹²

W is R ¹³ /

-N 'R ¹⁴ r is 0, R ¹² is -C (O) OR ¹⁶ , is wherein W is e H, R ¹³ or R ¹⁴ is H and the remaining R ¹³ or R ¹⁴ may be prepared by reaction of a compound of formula 1.0,

OH II I, -CC- _{(CH2) y} N _x r is R ¹² is H, R ¹³ and R ¹⁴ are both H, with the appropriate chloroformate

O ¹¹ ir

Cl-C-OR ¹⁶

TEA and CH ₂ C1 _2nd

Compounds of formula 25.0 and 26.0 wherein R ¹³ is selected from -SO 2 R or ^N-C (O) ^R18 may be prepared by reacting a compound of formula 25.0 or 26.0 with the appropriate sulfonyl chloride (R ¹⁷ SO2C1), or an appropriate acyl chloride (R ¹⁸ C (O) C1) with TEA in a suitable organic solvent (e.g. CH 2 Cl 2).

Compounds of Formula 1.0 wherein W is 1? ^H R ¹³

II I ^R CC- _{(CH2) r-N x}

² » ^{2 R} * ⁴ r is 1 or 2 and R ¹² is H, may be prepared by reacting a compound of Formula 20.0 or 22.0 with a suitably substituted carboxylic acid, for example DEC, HOBT and N-methylmorpholine, or reacting a compound of Formula 20.0 or 22.0 with a suitably substituted acid chloride.

For example, a compound of Formula 22.0 or 22.0 may be reacted with o

from propionic acid, wherein R ¹³ and R ¹⁴ are, for example, alkyl (e.g. methyl). When the aminocarboxylic acid is not commercially available, it can be prepared by reacting ethyl acrylate with a suitable amino compound (as described by Ahn KH et al. Tetrahedron Letters, 35 1875-1878 (1994)), followed by hydrolysis of the ester to the desired aminocarboxylic acid.

For example, a compound of Formula 20.0 or 22.0 can also be reacted with

OR ¹³

HO ^{/ s //} ^ ^S ^ ^{/ N rI4} of butyric acid, wherein R ¹³ and R ¹⁴ are, for example, alkyl (e.g. methyl). When the aminocarboxylic acid is not commercially available, a suitable acid chloride can be prepared similarly to Goel OP et al., Synthesis, p. 538 (1973). The acid chloride is then reacted with compounds of Formula 22.0 or 22.0 to form the corresponding compound

The chlorine atom can then be replaced with a suitable amine to give the desired compound.

When either R ¹³ and R ^{14 are} H, then the starting material will be protected aminocarboxylic acid

O ^H H

II I

HO-CC- _{(CH2) r} "N

^Z wherein Z is a suitable protecting group (e.g. BOC, CBZ (carbonylbenzyloxi) or TFA). Coupling of this protected aminocarboxylic acid with a compound of Formula 20.0 or 22.0 provides the corresponding amino-protected intermediate

The amino-protected intermediate (20.OB or 22.OB) is then alkylated and the protecting group is then removed by standard procedures known in the art.

Compounds of formula 1.0 wherein W is

OH II I - CC - (CH ₂ ) _{V -} R ¹⁵ R ¹² v is 0 and R ¹² is H, may be prepared by reacting a compound of Formula 20.0 or 22.0 with chloroacetyl chloride, TEA and CH 2 Cl 2,

27.0 is then replaced by a suitable nucleophile, R 15, using a suitable base (e.g. sodium carbonate) and preferably a suitable solvent (e.g. DMF).

Compounds of formula 1.0 wherein W is O 0

II-C- (CH 3) - C-R 22 z is 0 and R ²² is

R ²⁴

From —N'R ^25, it can be prepared from compounds of formula 20.0 or 22.0 by reaction with excess of pxallyl chloride and an amine

R ²⁴ hn _R 25

Compounds of formula 1.0 wherein W is

O í?

—C-- (CH 2 _Z —C - R "z is 1, 2, 3, 4 or 5 and R ²² is -OR ²³ , and R ²³ is, for example, alkyl, may be prepared by reacting a compound of Formula 20.0 or 22.0 with an appropriately substituted The corresponding acids (i.e., R ²³ is H) can be obtained by alkaline hydrolysis (e.g., NaOH) of the ester Compounds wherein R ²² is -NR ²⁴ R are substituted by a carboxylic acid which is protected as a monoester by a suitable alkyl or aryl group. ²⁵ , may be prepared by reacting a suitably substituted amine with the carboxylic acid obtained above, using DEC, HOBT and NMM For example, for compounds wherein z is 3, glutarate may be used

O o

OR ²³ (where R ²³ is alkyl, e.g. methyl), and a succinate can be used for compounds wherein z is 2

Ho'Vy ⁰ “

O (where R ²³ is alkyl, e.g. methyl), and malonate may be used for compounds wherein z is 1

HO

OR ²³ (wherein R ²³ is alkyl, e.g. ethyl).

Reaction Scheme 1 illustrates the preparation of compounds of the invention.

but are not intended to limit the scope of the invention.

DETAILED DESCRIPTION OF THE INVENTION

4 »

Example 1

At -20 ° C, 10 g (60.5 mmol) of ethyl 4-pyridyl acetate are mixed with 120 ml of dry CH ₂ Cl ₂ , 10.45 g (60.5 mmol) of MCPBA are added and the mixture is stirred at room temperature for 1 hour. 20 C and 67 hours at 25 ^e C. a further 3.48 g (20.2 mmol) of MCPBA and stir for 24 hours at 25 ° C. The mixture was diluted with CH ₂ Cl ₂ and washed with saturated aqueous NaHCO ₃ and then with water. The organic layer was dried over MgSO ₄ , evaporated in vacuo and the residue chromatographed (silica gel, 2% - 5.5% (10% NH ₄ OH in MeOH) / CH ₂ Cl ₂ ). 8.12 g of product are obtained. Mass Spectrum: MH ⁺ = 182.15.

Step B:

Combine 3.5 g (19.3 mmol) of the product of Step A, 17.5 mL of EtOH and 96.6 mL of 10% aqueous NaOH. The mixture was heated at 67 ° C for 2 hours, then 2 N aqueous HCl was added until pH = 2.37 and the mixture was evaporated in vacuo. Add 200 mL dry EtOH, filter through Celite® and wash the filter cake with dry EtOH (2 x 50 mL). The combined filtrates were evaporated in vacuo to give 2.43 g of the title compound.

Example 2 (a CHaktf-> _N _ ^<_ yy ^{CO2 H>} v_y

Said compound is prepared according to the procedure published in PCT International Application no. WO95 / 10,516th

Example 3

and

CO ₂ Et

Combine 14.95 g (39 mmol) of 8-chloro-ll- (1-ethoxycarbonyl-4-piperidinyl) -llH-benzo [5, 6] cyclohepta [l, 2-b] of pyridine and 150 mL of CH ₂ C1 ₂ , then 13.07 g (42.9 mmol) (nBu) _{4 of} NO _{3 are added} and the mixture is cooled to 0 ° C. A solution of 6.09 mL (42.9 mmol) of TFAA in 20 mL of CH 2 Cl 2 was slowly added dropwise over 1.5 hours. The temperature of the mixture was maintained at 0 ° C overnight, then washed sequentially with saturated aqueous NaHCO ₃ , water, and brine. The organic layer was dried over Na ₂ SO 4, evaporated in vacuo and the residue subjected to chromatography (silica gel, EtOAc / hexane, gradient elution). 4.32 g and 1.90 g of the two terminal compounds 3A (i) and 3A (ii) are obtained.

Mass spectrum of Compound 3A (i): MH ⁺ = 428.2; Mass spectrum of Compound 3A (ii): MH ⁺ - 428.3.

Step B:

Combine 22.0 g (51.4 mmol) of 3A (i) from Step A, 150 mL of 85% aqueous EtOH, 25.85 g (0.463 mol) of Fe powder and 2.42 g (21.8 mmol) of CaCl 2. ₂ . The mixture was heated at reflux overnight. To the mixture was added 12.4 g (0.222 mol) of Fe powder, 1.2 g (10.8 mmol) of CaCl _2, and the mixture was heated under reflux for 2 hours. To the mixture was added another 12.4 g (0.222 mole) of Fe powder and 1.2 g (10.8 mmol) of _CaCl2 and heat at reflux for a further 2 hours. The warm mixture was filtered through Celite®, the Celite® was washed with warm EtOH (50 mL) and the filtrate was evaporated in vacuo. To the residue was added 100 mL of anhydrous EtOH, the solution was concentrated and the residue was chromatographed (silica gel, MeOH / CH 2 Cl 2, gradient elution) to give 16.47 g of product.

Step C:

Combine 16.47 g (41.4 mmol) of the product of Step B and 150 mL of 48% aqueous HBr, then cool to -3 ° C. 18 ml of bromine was added slowly dropwise and then a solution containing 8.55 g (0.124 mol) of NaNO ₂ in 85 ml of water was slowly added dropwise. The mixture was stirred at -3 to 0 ° C for 45 minutes, then adjusted to pH 10 with 50% aqueous NaOH. The mixture was extracted with EtQAc, extracts washed with brine and dried over Na ₂ SO '. The dried extracts were evaporated and the residue was subjected to chromatography (silica gel, EtOAc / hexane, gradient elution). 10.6 g and 3.28 g of two 3C (i) 3C (ii) products are obtained.

Mass spectrum of Compound 3C (i): MH ⁺ = 461.2;

Mass Compound 3C (ii): MH ⁺ = 539.

Step D:

The product 3C (i) of Step C is hydrolyzed by dissolving in concentrated HCl and heating the mixture at 100 ° C for 16 hours. The mixture was cooled, neutralized with 1 M aqueous NaOH. Extraction with CH 2 Cl 2, drying of MgSO ₄ extracts, filtration and evaporation of the filtrate in vacuo gave the title compound.

Mass Spectrum: MH ⁺ = 466.9.

1.160 g (2.98 mmol) of the above product from Step D are dissolved in 20 mL of DMF and 0.3914 g (3.87 mmol) of 4-methylmorpholine, 0.7418 g (3, 87 mmol) DEC, 0.5229 g (3.87 mmol) HOBT and 0.8795 g (3.87 mmol) 1N-butoxycarbonylpiperidinyl-4-acetic acid. The mixture was stirred at room temperature for two days, concentrated in vacuo and the residue partitioned between CH 2 Cl 2 and water. The organic phase was washed with saturated aqueous NaHCO ₃ , 10% aqueous NaH ₂ PO _4, and brine. The organic phase was dried over MgSO ₄ , filtered and evaporated in vacuo. The residue was chromatographed (silica gel, 2% MeOH / CH ₂ Cl ₂ + NH ₃ ). 1.72 g of product with a melting point of 94.0 to 94.5 ° C are obtained.

Mass Spectrum: MH + = 616.3.

Elemental analysis: calculated - C, 60.54; H, 6.06; N, 6.83 found - C, 59.93; H, 6.62; N 7, 45.

Combine 1.67 g (2.7 mmol) of the product of Step E and 20 mL of CH ₂ C1J, the mixture was stirred at 0 ° C. After addition of 20 ml of TFA, the mixture was stirred for 2 hours and then basified with 1 N aqueous NaOH. Extraction with CH 2 Cl 2, drying the extract with MgSO ₄ , filtration and evaporation of the filtrate in vacuo gave 1.16 g of product, m.p. 140.2-140.8 ° C.

Mass Spectrum: MH ⁺ = 516.2

Example 4

25.86 g (55.9 mmol) of 4- (8-chloro-3-bromo-5,6-dihydro-11H-benzo [5,6] cyclohepta [1,2-a] ethyl ester) are added at -5 ° C. b] pyridin-11-ylidene) -1-piperidine-1-carboxylic acid and 250 ml of concentrated H ₂ SO ₄ , then 4.8 g (56.4 mmol) of NaNO _{3 are added} and the mixture is stirred for 2 hours. The reaction mixture was poured onto 600 g of ice and basified with a concentrated aqueous solution of ΝΗ ₄ ΟΗ. The mixture was filtered, washed with 300 mL of water and extracted with 500 mL of CH ₂ Cl ₂ . The extract was washed with 200 ml of water, dried over MgSO 4, filtered and evaporated in vacuo. The residue was chromatographed (silica gel, 10% EtQAc / GfeCl ₂ ). 24.4 g (86% yield) of product with a melting point of 165-167 ° C are obtained. Mass Spectrum: MH ⁺ = 506 (CI);

Elemental analysis: calculated - C 52.13; H, 4.17; N, 8.29

At 20 ° C, 20 g (40.5 mmol) of the product of Step A and 200 ml of concentrated H ₂ SO ₄ are mixed, then the mixture is cooled to 0 ° C. 7.12 g (24.89 mmol) of 1,3-dibromo-5,5-dimethylhydantoin are added and the mixture is stirred at 20 ° C for 3 hours. The mixture was cooled to 0 ° C, an additional 1.0 g (3.5 mmol) of dibromohydantoin was added and the mixture was stirred at 20 ° C for 2 hours. The reaction mixture was poured onto 400 g of ice, basified at 0 ° C with concentrated aqueous NH ₄ OH and the resulting solid was collected by filtration. The solid is washed with 300 ml of water, resuspended in 200 ml of acetone and filtered to give 19.79 (85.6% yield) of the product, mp 236-237 ° C. Mass Spectrum: MH ⁺ = 584 (CI);

Elemental analysis: calculated - C 45.11; H, 3.44; N, 7.17 found - C, 44.95; H, 3.57; N, 7.16.

Step C:

At 50 ° C, 25 g (447 mmol) of Fe filin, 10 g (90 mmol) of CaCl ₂ and 20 g (34.19 mmol) of a suspension of the product of Step B in 700 ml of EtOH / water (90:10) are mixed. . The mixture was refluxed overnight, then filtered through Celite® and the filter cake was washed with 2 x 200 mL warm EtOH. The combined filtrates were evaporated in vacuo and the residue was extracted with 600 ml CH ₂ C1 _2, washed with 300 mL of water and dried over MgSO _fourth Filtration, evaporation in vacuo and then chromatography (silica gel, 30% EtOAc / CH ₂ Cl ₂ ) gave 11.4 g (60% yield) of the product, mp 211-212 ° C. Mass Spectrum: MH + = 554 (CI);

Elemental analysis: calculated - C 47.55; H, 3.99; N, 7.56 found - C, 47.45; H, 4.31; N, 7.49.

To a solution of 8 g (116 mmol) of NaNO ₂ in 120 mL of concentrated HCl (aqueous solution) cooled to -10 ° C was slowly added portionwise 20 g (35.9 mmol) of the product from Step C. The resulting mixture was stirred at at 0 ° C and then 150 ml (1.44 mol) of 50% H ₃ PO ₂ are slowly added dropwise over 1 hour at 0 ° C. The mixture was stirred at 0 ° C for 3 hours and then poured onto 600 g of ice, basified with concentrated aqueous NH ₄ OH and extracted with 2 x 300 mL CH ₂ Cl ₂ . The extracts were combined and dried over MgSO ₄ , filtered and evaporated in vacuo. The residue was chromatographed (silica gel, 25% EtOAc / hexane) to give 33.67 g (70% yield) of the product, mp 163-165 ° C. Mass Spectrum: MH ⁺ = 539 (CI);

Elemental analysis: calculated - C 48.97; H, 4.05; N, 5.22 found - C, 48.86; H, 3.91; N, 5.18.

Combine 6.8 g (12.59 mmol) of the product of Step D and 100 mL of concentrated aqueous HCl, and stir at 85 ° C overnight. The reaction mixture was cooled, poured onto 300 g of ice, basified with concentrated aqueous NH ₄ OH solution and extracted with 2 x 300 mL of CH ₂ Cl ₂ . The extracts were dried over MgSO ₄ , filtered and evaporated in vacuo. The residue was chromatographed (silica gel, 10 MeOH / EtOAc + 2% aqueous NH ₄ OH) to give 5.4 g (92% yield) of the product, mp 172-174 ° C. Mass Spectrum: MH ⁺ = 467 (FAB);

I

Elemental analysis: calculated - C 48.69; H, 3.65; N, 5.97 Found - C, 48.83; H, 3.80; N, 5.97.

Step F:

Following essentially the same procedure of Step C of Example 5 below, the compound of Step E above is reacted with 1-N-t-butoxycarbonylpiperidinyl-47-acetic acid to provide:

C _{(CH3) 3}

Step G:

Following essentially the same procedure of Step D of Example 5 below, the protecting group was removed from the compound of Step F to give the compound of Example 4.

Example 5

NH

Step A:

Hydrolysis of 2.42 g of 4- (8-chloro-3-bromo-5,6-dihydro-11H-benzo [5,6] cyclohepta [1,2-b] pyridin-11-ylidene) -1-piperidine-1-carboxylic acid ethyl ester Following the same procedure described in Example D, Step D, 1.39 g (69% yield) of the product was obtained.

Step B:

Combine 1 g (2.48 mmol) of the product of Step A and 25 mL of dry toluene, add 2.5 mL of 1 M DIBAL in toluene, and heat the mixture at reflux. After 0.5 h, an additional 2.5 mL of 1 R DIBAL in toluene was added and the mixture was heated at reflux for 1 h. (The reaction was monitored by TLC using 50 S MeOH / CH ₂ Cl ₂ + aqueous NH ₄ OH). The reaction mixture was cooled to room temperature, 50 mL of 1 N aqueous HCl solution was added and stirred for 5 minutes. To the mixture was added 100 mL of 1 N aqueous NaOH, and the mixture was then extracted with EtOAc (3 x 150 mL). The extracts were dried over MgSO 4, filtered, evaporated in vacuo to give 1.1 g of the title compound.

Step C:

0.501 g (1.28 mmol) of the compound from Step B and 20 ml of dry DMF are mixed, then 0.405 g (1.646 mmol) of 1-N-t-butoxycarbonylpiperidinyl-4-acetic acid, 0.319 g (1.664 mmol) of DEC, 0.225 g (1.664 mmol) of HOBT and 0.168 g (1.664 mmol) of 4-methylmorpholine. The mixture was stirred at room temperature overnight. The reaction mixture was then evaporated in vacuo and partitioned between 150 mL of CH ₂ Cl ₂ and 150 mL of saturated aqueous NaHCO 3. The aqueous phase was extracted with another 150 mL of CH ₂ C1 _2nd The organic phase is dried over MgSO 4 and evaporated in vacuo. The residue is chromatographed (silica gel, 500 ml hexane, 111% MeOH / CH ₂ Cl ₂ + 0.1% aqueous solution ΝΗ ₄ ΟΗ, then 1 1 2% MeOH / CH ₂ Cl ₂ + 0.1% aqueous NH 4 solution). OH). . 0.575 g of product is obtained, m.p. 115-125 ° C. Mass Spectrum: NH ⁺ = 616;

Step D:

0.555 g (0.9 mmol) of the product of Step C and 15 mL of CH ₂ Cl ₂ are mixed, cooled to 0 ° C. TFA (15 mL) was added and the mixture was stirred at 0 ° C for 2 h. The reaction mixture was evaporated at 40-45 ° C under vacuum and partitioned between 150 mL of CH ₂ Cl ₂ and 100 mL of saturated aqueous NaHCO ₃ . The aqueous layer was extracted with 100 mL of CH 2 Cl 2 and the combined extracts were dried over MgSO ₄ . Evaporation in vacuo gave 0.47 g of product, m.p. 140-150 ° C. Mass Spectrum: NH ⁺ = 516.

(racemic (+) and (-) isomers)

Step A:

br

O och ₂ cii ₃

Combine 16.6 g (0.03 mol) of the product of Step D of Example 4 with CH ₃ CN: H ₂ O = 3: 1 (212, 65 mL CH ₃ CN and 70.8 mL water) to give the mixture was stirred overnight at room temperature. Then 32.833 g (0.153 mol) of NaIO ₄ and 0.31 g (2.30 mmol) of RuO _{2 are added} . The mixture was stirred at room temperature to give 1.39 g (69% yield) of product. (The addition of RuO ₂ is accompanied by an exothermic reaction, the temperature rises from 20 to ° C). The mixture was stirred for 1.3 hours (temperature after about 30 min at 25 ^e C), and filtered and the removed solids washed with CH ₂ C1 _2nd The filtrate was concentrated in vacuo and the residue was dissolved in CH ₂ C1 _2nd After filtering to remove insoluble solids, the particles are washed with CH ₂ Cl ₂ . The filtrate was washed with water, evaporated to a volume of 200 ml and washed with the decolorizing solution and then with water. Extract with 6 N aqueous HCl. The aqueous extracts were cooled to 0 ° C and a 50% aqueous NaOH solution was added slowly so that the temperature did not rise to more than 30 ° C and a pH = 4 was reached. The solution was extracted twice with CH ₂ Cl ₂ , dried over MgSO 4. and evaporated in vacuo. The residue was suspended in 20 mL of EtOH and the mixture was cooled to 0 ° C. The resulting solid was filtered and dried under vacuum. 7.95 g of product is obtained. ^J 1 HNMR (CDCl _3, 200 MHz): 8.7 (s, 1H); 7.85 (m,

6H); 7.5 (d, 2 H); 3.45 (m, 2 H); 3.15 (m, 2 H).

Combine 21.58 g (53.75 mmol) of the product of Step A and 500 mL of anhydrous EtOH: toluene (1: 1), add 1.43 g (37.8 mmol) of NaBH4 and heat the mixture for 10 min. minutes under reflux, then cooled to 0 ° C, water (100 ml) was added and the pH was adjusted to 4.5 with aqueous HCl so that the temperature did not rise above 10 ° C. The organic layer was washed with brine (3 x 50 mL) and then dried over Na ₂ SO _4. Evaporation of the solution in vacuo gave a residue (24.01 g) which was subjected to chromatography ( silica gel, 30% hexane / CH ₂ Cl ₂₎ to give the product. Impure fractions were purified by further chromatography to afford a total of 18.57 g of product. ^X H NMR _(DMSO-d6, 400 MHz): 8.5 (s 7.9 (s, 1H); 7.5 (dd, 2H); 6.2 (s, 1H); 6.1 (s, 1H);

1H); 3.5 (m, 1 H); 3.4 (m, IH); 3.2 (m, 2 H).

Step C:

18.57 g (46.02 mmol) of the product of Step B and 500 mL of CHCl 3 are mixed / 6.70 mL (91.2 mmol) of SOCl _{2 are added} and the mixture is stirred for 4 hours at room temperature. To the mixture was added over 5 minutes a solution of 35.6 g (0.413 mole) of piperazine in 800 mL of THF and stirred for 1 hour at room temperature, then heated under reflux overnight and cooled to room temperature, diluted with 1 1 _CH2 C1 ₂ . The mixture was washed with water (5 x 200 mL) and the aqueous phase was extracted with CHCl ₃ (3 x 100 mL). Combine the organic solutions, wash with brine (3 x 200 mL) and dry over MgSO ₄ . The solution was evaporated in vacuo and the residue chromatographed (silica gel, gradient 5%, 7.5%, 10%).

MeOH / CH ₂ Cl ₂ + NH ₄ OH) to give 18.49 g of the title compound as a racemic mixture.

Η

The racemic compound of Step C was separated by chiral chromatography (Chiralpack AD, 5 cm x 50 cm column, flow rate 100 mL / min, 20% iPrOH / hexane + 0.2% diethylamine) to give 9.14 g of (+) - isomer and 9.30 g of the (-) - isomer.

Physical chemical data of the (+) - isomer: mp = 74.5 - 77.5 ° C, mass spectrum MH ⁺ = 471.9; [α] ²⁵ D = + 97.4 ° (8.48 mg / 2 mL MeOH).

Physical chemical data of (-) - isomer: mp = 82.9-84.5 ° C, mass spectrum MH ⁺ = 471.8; [α] ²⁵ D = -97.4 ° (8.32 mg / 2 mL MeOH).

Step E:

br

(-) - isomer,

Combine 3.21 g (6.80 mmol) of the (-) - isomer from Step D and 150 mL of anhydrous DMF. 2.15 g (8.8 mmol) of 1 N-butoxycarbonylpiperidinyl-4-acetic acid, 1.69 g (8.8 mmol) of DEC, 1.19 g (8.8 mmol) of HOBT and 0.97 are added to the mixture. ml (8.8 mmol) of N-methylmorpholine. The mixture was stirred at room temperature overnight. The DMF was removed by evaporation in vacuo and 50 mL of saturated aqueous NaHCO _{3 was added} . The mixture was extracted with CH ₂ Cl ₂ (2 x 250 mL), the extracts were washed with 50 mL brine and dried over MgSO ₄ . The extract was evaporated in vacuo and the residue chromatographed (silica gel, 2% MeOH / CH ₂ Cl ₂ + 10% NH ₄ OH). 4.75 g of product with a melting point of 75.7-78.5 ° C are obtained. Mass Spectrum: MH ⁺ = 697; [α] ²⁵ D = -5.5 ° (6.6 mg / 2 mL MeOH).

Step F:

Combine 4.70 g (6.74 mmol) of the product of Step E and 30 mL of MeOH, then treated for 1 hour with 10 ml portions of 50 mL of 10% H ₂ SO '/ dioxane. The reaction mixture is poured into 50 ml of water and 15 ml of a 50% aqueous NaOH solution are added to bring the pH to about 10-11. The precipitated solid is removed by filtration and the filtrate is extracted with CH ₂ Cl ₂ (2 x 250 ml). Evaporation in vacuo, the aqueous layer was removed from the MeOH and extract os / CRT 250 ml PGI £ ci _second The combined extracts were dried over MgSO 4 and evaporated in vacuo to give the product, mp 128.1-131.5 ° C. Mass Spectrum: MH ⁺ = 597; [α] ²⁵ ο = -6.02 ° (9.3 mg / 2 mL MeOH).

Example 7

Step A:

15 g (38.5 mmol) of 4- (8-chloro-3-bromo-5,6-dihydro-11 H -benzo [5,6] -cyclohepta [1,2-b] ethyl ester are mixed at -5 ° C. pyridin-11-ylidene) -1-piperidine-1-carboxylic acid and 150 ml of concentrated H ₂ SO 4, then 3.89 g (38.5 mmol) of KNO 3 are added and the mixture is stirred for 4 hours. The reaction mixture was poured onto 3 L of ice. and basified with 50% aqueous NaOH. Extraction of CH ₂ Cl ₂ , drying over MgSO ₄ , filtration and evaporation in vacuo gave a residue which was recrystallized

from acetone to give 6, 69 g product. ^X H NMR (CDCl ^ 200 MHz): 8 ^ 5 (s, 1H); 7.75 (s, 1 H); 7.6 (s, 1H); 7.35 (s, 1H); 4.15 (qz 2H) ; 3.8 (m, 2 H); 3.5 to 3.1 (m, 4H); 3.0 to 2.8 (m, 2H); 2 6-2.2 (m, 4H); 1.25 (t,

3H).

Step B:

Combine 6.69 g (13.1 mmol) of the product of Step A and 100 mL of 85% EtOH / water, then add 0.66 g (5.9 mmol) of CaCl ₂ , 6.56 g (117.9 mmol). Fe and the mixture was heated at reflux overnight. Filter the warm reaction mixture through Celite® and rinse the filter cake with warm EtOH. Evaporation of the filtrate in vacuo afforded 7.72 g of product. Mass Spectrum: MH ⁺ = 478.0.

Combine 7.70 g of the product of Step B and 35 mL of HOAc, then add 45 mL of a solution of Br ₂ in HOAc and stir overnight at room temperature. To the mixture was added 300 mL of 1 N aqueous NaOH, then 75 mL of 50% aqueous NaOH, and the mixture was extracted with EtOAc. The extract was dried over MgSO 4 and evaporated in vacuo. The residue was chromatographed (silica gel, 20-30% EtOAc / hexane) to give 3.47 g of the product (along with other

1.28 g of partially pure product). Mass spectrum:

MH ⁺ = = 555.9. ^H NMR (CDCl3, 300 MHz): 8 Δ (s, 1H); 7 j -5 (s, 1 H); 7.15 (s, 1H) ; 4.5 (s, 2H); 4.15 (m, 3H); 3.8 (br s, 2H); 3.4 to 3.1 (m, 3H) , 2.9 to 2.75 (m, 1 H); 2.7 until 2.5 (m, 2H); 2,4 to 2.2 (m, 2H); 1.25 (m, 3H). step D: •

0.557 g (5.4 mmol) of t-butyl nitrite, 3 ml of DMF are added and the mixture is heated to 60-70 ° C. A mixture of 2.00 g (3.6 mmol) of the product of Step C and 4 mL of DMF was then added slowly dropwise. The mixture was cooled to room temperature. An additional 0.64 ml of t-butyl nitrite is added at 40 ° C and the mixture is heated at 60-70 ° C for 0.5 hours. The mixture was cooled to room temperature and poured into 150 ml of water, then extracted with CH ₂ Cl ₂ , dried over MgSO 4 and evaporated in vacuo. The residue was chromatographed (silica gel, 10-20% EtOAc / hexane) to give 0.74 g of product. Mass Spectrum: MH ⁺ = 541.0.

^J 1 HNMR (CDCl _3, 200 MHz): 8.52 (s, 1H); 7.5 (d, 2 H); 7.2 (s, 1 H); 4.15 (q, 2 H); 3.9-3.7 (m, 2H); 3.5 to 3.1 (m, 4H); 3.0 to 2.5 (m, 2H); 2.4-2.2 (m, 2H); 2.1-1.9 (m, 2H); 1,2fef (t, 3H). about

Step E:

Combine 0.70 g (1.4 mmol) of the product of Step D and 8 mL of concentrated aqueous HCl, and heat the mixture at reflux overnight. Was added 30 ml of 1N aqueous NaOH, 5 mL of 50% aqueous NaOH and extracted with CH ₂ C1 _2nd The extract was dried over _MgSO4 and concentrated in vacuo to give 0.59 g of the product, mp 123.9 to 124.2 C. ^e MH ⁺ = 468.7.

Step F:

6.0 g (12.8 mmol) of the compound of Step E were reacted with 3.78 g (16.6 mmol) of 1-N-butoxycarbonylpiperidinyl-4-acetic acid according to the procedure of Example 5, Step C. 8.52 g of product are obtained. Mass Spectrum: MH + = 694.0 (FAB). ¹ H NMR (CDCl ₃ , 200 MHz): 8.5 (d, 1H); 1.5 (d, 2H); 7.1 (d, 1H); 4.15 to 3.9 (m, 3H); 3.8 to 3.6 (m, 1H); 3.5 to 3.15 (m, 3H); 2.9 (d, 2 H); 2.8-2.5 (m, 4H); 2.4-1.8 (m, 6H); 1.8 to 1.6 (br d, 2H); 1.4 (s. 9H); 1.25 to 1.0 (m, 2H).

Step G:

br

ABOUT

8.50 g of the product of Step F and 60 mL of CH 2 Cl 2 are combined, cooled to 0 ° C. Add 55 mL of TFA and stir at 0 ° C for 3 hours, then add 500 mL of 1 N aqueous NaOH followed by 30 mL of 50% aqueous NaOH. The mixture was extracted with CH 2 Cl 2, the extract was dried over MgSO ₄ and evaporated in vacuo to give 7.86 g of product. Mass Spectrum: MH ⁺ = 593.9 (FAB). 1 H NMR (CDCl ₃ , 200 MHz): 8.51 (d, 1H); 7.52 (dd, 2 H); 7.20 (d, IH); 4.1 to 3.95 (m, 2H); 3.8 to 3.65 (m, 2H); 3.5 to 3.05 (m, 5H); 3.0 to 2.5 (m, 6H); 2.45 to 1.6 (m, 6H); 1.4-1.1 (m, 2H).

Example 8

br

NH (racemic mixture and also (+) - and (-) - isomers)

Step A:

A toluene solution of 8.1 g of the compound of Step E of Example 7 was prepared and 17.3 ml of a 1M solution of DIBAL in toluene was added thereto. The mixture was heated to reflux and slowly, an additional 21 mL of a 1M DIBAL / toluene solution was added dropwise over 40 minutes. The reaction mixture was cooled to 0 ° C and 700 mL of 1 M aqueous HCl was added. The organic layer was separated, the organic phase was removed, the aqueous phase was washed with CH ₂ Cl ₂ , the extract was removed, then the aqueous layer was basified by addition of 50% aqueous NaOH. Extraction with CH ₂ C1 _2, dry the extract over MgSO <and evaporated in vacuo to give 7.30 g of the title compound, which is a racemic mixture of enantiomers.

The racemic compound of Step A was separated by preparative chiral chromatography (Chiralpack AD, 5 cm x 50 cm column, 20% iPrOH / hexane + 0.2% diethylamine) to give the (+) - isomer and (-) - isomer of the title compound. .

Physical chemical data of the (+) - isomer: mp = 148.8 ° C, mass spectrum MH ⁺ = 469; [α] ²⁵ D = + 65.6 ° (12.93 mg / 2 mL MeOH).

Physical chemical data of the (-) - isomer: mp - 112 ° C, mass spectrum MH ⁺ = 469; [α] ²⁵ D = -65.2 ° (3.65 mg / 2 mL MeOH).

Step C:

Using the same procedure described for Step C in Example 5, 1.33 g of the (+) - isomer of the compound of Step B of Preparative Example 8 was reacted with 1.37 g of 1-N-butoxycarbonylpiperidinyl-4-acetic acid to give 2. 78 g of product. Mass Spectrum: MH + = 694.0 (FAB); [.alpha.] D @ ²⁵ = + 34.1 DEG (5.45 mg / 2 mL MeOH).

Using the same procedure described for Step D in Example 5, 2.78 g of the product of Step C was treated to give 1.72 g of the product with a melting point of 104.1 ° C. Mass Spectrum: MH + = 594.0; [α] ²⁵ D = + 53.4 ° (11.42 mg / 2 mL MeOH).

Example 9

(racemic mixture and also and (-) - isomers)

Step A:

40.0 g (0.124 mol) of the ketone are mixed with 200 ml of H ₂ SO ₄ and the mixture is cooled to 0 ° C. 13.78 g (0.136 mol) of KNO ₃ are slowly added over 1.5 hours, the reaction mixture is warmed to room temperature and stirred overnight. The reaction procedure is the same as in Step A of Preparative Example 4. Chromatography (silica gel, 20%, 30%, 40%, 50% EtOAc / hexane, then 100% EtOAc) yields 28 g of the 9-nitro product along with a smaller amount of 7- nitro product and 19 g of a mixture of 7-nitro and 9-nitro compounds.

.1

Step B:

Using the same procedure described in Step C of Example 4, 28 g (76.2 mmol) of the 9-nitro product from Step A, 400 mL of 85% EtOH / H ₂ O, 3.8 g (34.3 mmol) of CaCl were reacted. ₂ and 38.28 g (0.685 mol) Fe to give 24 g of the product.

Step C:

13 g (38.5 mmol) of the product of Step B, 140 mL of HOAc were added and a solution of 2.95 mL (57.8 mmol) of Br ₂ in 10 mL of HOAc was added slowly over 20 minutes. The reaction mixture was stirred at room temperature and then evaporated in vacuo. CH ₂ Cl ₂ and water are added to the residue, then the pH is adjusted to 8-9 with 50% aqueous NaOH solution. The organic layer is washed with water, then brine and dried over Na ₂ SO ₄ . Evaporation in vacuo gave 11.3 g of product.

100 mL of concentrated HCl (aqueous) was cooled to 0 ° C, 5.61 g (81.4 mmol) of NaNO _{2 was added} and the mixture was stirred for 10 minutes. 11.3 g (27.1 mmol) of the product of Step C was added slowly in portions, and the mixture was stirred at 0-3 ° C for 2.25 hours, 180 mL of 50% aqueous H ₃ PO was added dropwise. ₂ and allowed to stand at 0 ° C overnight. Then, slowly add dropwise 150 ml of 50% NaOH over 30 minutes to reach pH 9 and extract with CH ₂ Cl ₂ . The extract was washed with water, then brine and dried over Na ₂ SO ₄ . Concentrate in vacuo to a residue and chromatograph (silica gel, 2% EtOAc / CH ₂ Cl ₂ to give 8.6 g of product.

Mix 8.6 g (21.4 mmol) of the product of Step D with 300 mL of MeOH and cool to 0-2 ° C. 1.21 g (32.1 mmol) of NaBH _{4 were added} and the mixture was stirred at 0 ° C for 1 hour. An additional 0.121 g (3.21 mmol) of NaBH _{4 was added} , and the mixture was stirred at 0 ° C for 2 hours and then allowed to stand overnight at 0 ° C. The mixture was concentrated in vacuo and partitioned between CH ₂ C1 ₂ and water. The organic phase was separated, evaporated in vacuo (50% product).

° C) to give 8.2 g of the product.

Combine 8.2 g (20.3 mmol) of the product of Step E and 160 mL of CH ₂ C1 _2, cooled to 0 ° C and slowly over 30 minutes dropwise, ^'1 was added 14.8 ml (203 mmol) SOCl ₂ . The mixture was warmed to room temperature and stirred for 4.5 hours, then evaporated in vacuo, CH ₂ Cl ₂ was added to the residue, and the solution was washed with 1 N aqueous NaOH, then brine and dried over Na ₂ SO ₄ . The solution was evaporated in vacuo, then dry THF was added

and 8.7. g (101 mmol) of piperazine, the mixture was stirred at room temperature overnight. The mixture was evaporated in vacuo, CH ₂ Cl ₂ was added to the residue, the solution was washed with 0.25 N aqueous NaOH, water and then brine. The solution was dried over Na ₂ SO ₄ and evaporated in vacuo to give 9.46 g of crude product. Chromatography (silica gel, 5% MeOH / CH ₂ Cl ₂ + NH ₃ ) gave 3.59 g of the racemic compound. ^X 1 HNMR (CDCl _3, 200 MHz): 8.43 (d, 1H); 7.55 (d, IH); 7.45 (d, IH); 7.11 (d, IH); 5.31 (s, 1 H); 4.86 to 4.65 (m, 1H); 3.57 to 3.40 (m, 1H); 2.98 to 2.55 (m, 6H); 2.45 to 2.20 (m, 5H).

Step G - Separation of enantiomers:

WITH-(-)

The racemic compound from Step F (5.7 g) was chromatographed as described in Step D of Example 6 using 30% iPrOH / hexane + 0.2% diethylamine. Obtained

2.88 g of the R - (+) - isomer and 2.77 g of the S - (-) - isomer of the title compound.

Physical chemical data of the R - (+) - isomer: MH ⁺ = 470; [α] _D = + 12.1 ° (10.9 mg / 2 mL MeOH).

Physical chemical data of S - (-) - isomer: mass spectrum 1 H + = 470.0; [α] ²⁵ D = -13.2 ° (11.51 mg / 2 mL MeOH).

Step H:

In the same manner as in steps C and D of Example 5, the racemic compound of Step 9 was obtained from the racemic compound of Step F. Similarly, using the (-) - or (+) - isomer of Step G, the (-) - or (+) - isomer of the compound was obtained. of Example 9.

Example 10 (racemic

Step A:

At 20 ° C, 13 g (33.3 mmol) of the compound of Step E of Example 4 and 300 ml of toluene are mixed, then 32.5 ml (32.5 mmol) of a ⁴ M solution of DIBAL in toluene are added. The mixture was heated at reflux for 1 hour, cooled to 20 ° C, an additional 32.5 ml of 1M DIBAL solution was added and refluxed for 1 hour. The mixture is cooled to 20 ° C and poured into a mixture of 400 g of ice, m.p.

500 mL EtOAc and 300 mL 10% aqueous NaOH. The aqueous layer was extracted with CH 2 Cl 2 (3 x 200 mL), the organic layer was dried over MgSO ₄ , then evaporated in vacuo and the residue chromatographed (silica gel, 12% MeOH / CH ₂ Cl ₂ + 4% NH ₄ OH) to give 10.4 g of the title compound are obtained in racemic form. Mass Spectrum: MH + = 469 (FAB); partial ^lH NMR (CDCl3, 400 MHz): 8.38 (s, 1H); 7.57 (s, 1 H); 7.27 (d, IH); 7.06 (d, IH); 3.95 (d, IH).

Step B - Separation of enantiomers:

The racemic compound of Step A was separated by preparative chiral chromatography (Chiralpack AD, 5 cm x 50 cm column, 5% iPrOH / hexane + 0.2% diethylamine) to give the (+) - isomer and (-) - isomer of the title compound. .

Physical chemical data of the (+) - isomer: MH ⁺ = 469 (FAB); [α] ²⁵ D = + 43.5 ° (c - 0.402; EtOH); full * 1 HNMR (CDCl _3, 400 MHz): 8.38 (s, 1H); 7.57 (s, 1 H); 7.27 (d, IH); 7.05 (d, IH); 3.95 (d, IH).

Physical chemical data of the (-) - isomer: MH + = 469 (FAB); [α] ²⁵ D = -41.8 ° (c = 0.328; EtOH); partially ⁷ H NMR (CDCl ₃ , 400 MHz): 8.38 (s, 1H); 7.57 (s, 1 H); 7.27 (d, IH); 7.05 (d, IH); 3.95 (d, IH).

Step C:

According to the method of Step H of Example 9, the racemic compound, the (+) - isomer or the (-) - isomer of the compound of Example 10 was obtained.

compound

H is prepared according to the procedures of Example 40 of WO 95/10516 (published April 20, 1995 '), following the same procedures described in Example 193 of WO 95/10516.

The (+) - and (-) - isomers can be separated by the same procedure as in Step D of Preparative Example 6.

Physical chemical data for R- (+) - isomer: ¹³ C M4R (CDCl ₃ ): 155.8 (C); 146.4 (CH); 140.5 (CH); 140.2 (C); 136.2 (C); 135.3- (C); 133.4 (C); 132.0 (CH); 129.9 (CH); 125.6 (CH); 119.3 (C); 79.1 (CH); 52.3 _(CH2); 52.3 (CH); 45.6 _(CH2); 45.6 _(CH2); 30.0 _(CH2); 29.8 _(CH2); [α] ²⁵ D = + 25.8 ° (8.46 mg / 2 mL MeOH).

Physical chemical data of S - (-) - isomer: NMR (ClCl 3):

155.9 (C); 146.4 (CH); 140.5 (CH); 140.2 (C); 136.2 (C); 135, 3 (C); 133.3 (C); 132.0 (CH); 129.9 (CH); 125.5 (CH); 119.2 (C); 79.1 (CH); 52.5 _(CH2); 52.5 (CH); 45.7 _(CH2); 45.7 (CH ₂ ) 1 30.0 _(CH2); 29.8 _(CH2); [α] _D = -27.9 ° (8.90 mg / 2 mL of MeOH).

By essentially the same procedure as in steps C and D of Example 5, the racemic compound, the (+) - isomer or the (-) - isomer of Example 11 was obtained from the corresponding racemic compound of the (+) - isomer or the (-) - isomer of the compound.

Example 12 x NH ₂ r . ^H 0 Y 2 O 1 ^N Y ^CH =

CH,

Follow the procedure described in Collect. Czech. Chem. Comm. (1990) 55, 2086. 0.2 g (0.915 mmol) of (aminooxy) acetic acid hemihydrochloride and 0.2 g (3 mmol) of acetone are dissolved in 2 ml of pyridine and allowed to stand for 18 hours. The mixture was concentrated in vacuo and partitioned between ethyl acetate and 1 N HCl. The organic layer was dried over magnesium sulfate and evaporated in vacuo to give a white solid, mp 77.3-78 ° C.

Example 13 ^Η ° γ \ / ^Ο >

NH,

HO

CH,

CH,

The procedure of Example 12 was followed, but instead of (aminooxy) acetic acid, 2-aminooxypropionic acid heme hydrochloride was used to give the product as a colorless oil.

Example 14

The procedure of Example 12 was followed but 4-pyridinecarboxaldehyde oxide was used in place of acetone to give the product, which was recrystallized from water to give a white solid & mp 227-228 ° C.

Example 15

The procedure of Example 12 was followed but 2-hydroxybenzaldehyde was used in place of acetone to give the product as a white solid, mp 152-153.5 ° C.

(Example 8) (0.149 g, 0.25 mmol) was mixed with 1-hydroxybenzotriazole hydrate (0.067 g, 0.5 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.096 g, 0.5 mmol) N-BOC-glycine (0.087 g, 0.5 mmol) and anhydrous dimethylformamide (5 mL). The resulting mixture was stirred overnight under nitrogen at room temperature. Evaporation in vacuo yielded an oil which was diluted with dichloromethane, washed with 1 M HCl and 1 M aqueous NaOH, then dried over anhydrous MgSO ₄ . Filtration and evaporation in vacuo gave the compound of formula 2.0 (+ - isomer) (0.16 g, 85%, mp 116 123 ° C).

Example 2

To compound 2.0 (Example 1) (0.145 g) dissolved in anhydrous dichloromethane (10 mL) was added trifluoroacetic acid (2 mL) and the resulting solution was stirred at room temperature for 1 hour. 50% aqueous NaOH was added slowly followed by dichloromethane and brine. The mixture was shaken well, the organic phase was separated and dried over anhydrous MgSO ₄ . Filtration and evaporation in vacuo gave the compound of formula 16.0 (+ -isomer) (0.086 g, 68%, mp 131-138 ° C).

ch ₃ ch ₃

Compound of Formula 28.0 (Example 8) (0.10 g, 0.17 mmol) m.p.

was mixed with 1-hydroxybenzotriazole hydrate (0.045 g, 0.34 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrate.

I with hydrochloride (0.064 g, 0.34 mmol), N-tert-butoxycarbonyl-L-alanine (0.064 g, 0.34 mmol) and anhydrous dimethylformamide (10 mL). The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. Concentration in vacuo yielded an oil which was diluted with dichloromethane and washed with 1 M

HCl and 1 M aqueous NaOH and then dried over anhydrous MgSO ₄ . Filtration and concentration in vacuo afforded the compound of formula 3.0 (+ -isomer) (0.095 g, 74%, mp 135-142 ° C).

To compound 3.0 (Example 3) (0.09 g) dissolved in anhydrous dichloromethane (10 mL) was added trifluoroacetic acid (1 mL). The resulting solution was stirred at room temperature for 1 hour. 50% aqueous NaOH was added slowly, followed by dichloromethane and brine. The mixture was shaken well, the organic phase was separated and dried over anhydrous MgSO ₄ . Filtration and concentration in vacuo gave the compound of formula 17.0 (+ -isomer) (0.053 g, 68%, mp 122.7-128 ° C).

Example 5

Compound 28.0 (Example 8) (0.10 g, 0.17 mmol) was mixed with 1-hydroxybenzotriazole hydrate (0.045 g,

0.34 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.064 g, 0.34 mmol), N-tert-butoxycarbonyl-D-alanine (0.064 g, 0.34 mmol) and anhydrous dimethylformamide (10 mL). The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. Concentration in vacuo yielded an oil which was diluted with dichloromethane, washed with 1 M HCl and 1 M aqueous NaOH, then dried over anhydrous MgSO ₄ . Filtration and concentration in vacuo gave the compound of formula 4.0 (+ -isomer) (0.104 g, 81%, mp 135.1-142.3 ° C).

To a compound of formula 4.0 (Example 5) (0.10 g) dissolved in anhydrous dichloromethane (10 mL) was added trifluoroacetic acid (1 mL) and the resulting solution was stirred at room temperature for 1 hour. 50% aqueous NaOH was added slowly followed by dichloromethane and brine. The mixture was shaken well, the organic phase was separated and dried over anhydrous MgSO ₄ . Filtration and concentration in vacuo gave the compound of formula 18.0 (+ -isomer) (0.056g, 64%, mp 103 ° C).

ci (5.0)

The compound of formula 5.0 (+ -isomer) was prepared following a similar procedure as in Examples 1, 3 and 5, by reacting the compound of Formula 28.0 '(Example 8) with the amino acid N tert -butoxycarbonyl-L-phenylalanine.

Yield: 76%, mp 128.6-134 ° C.

The compound of formula 6.0 (+ -isomer) was prepared following a similar procedure to that described in Examples 1, 3 and 5 by reacting a compound of Formula 28.0 (Example 8) with the amino acid N (alpha) -tert-butoxycarbonyl-L-histidine.

Yield: 32%, mp 96.0-99.7 ° C.

Example 9

The compound of formula 7.0 (+ -isomer) was prepared following a similar procedure to that described in Examples 1, 3 and 5 by reacting a compound of formula 28.0 (Example 8) with the amino acid N (alpha) -tert-butoxycarbonyl-L-proline.

Yield: 52%, m.p. 110 ° C.

Example 10

The compound of formula 8.0 (+ -isomer) was prepared in a similar manner to that described in Examples 2, 4 and 6 from the compound of formula 5.0 (Example 7).

Yield: 70%, mp 116-119 ° C.

Compound 10.0 (+ -isomer) was prepared from compound 6.0 (Example 8) by a similar procedure to that described in Examples 2, 4 and 6. Yield 51%, mp 101.0 ° C.

100

Example 12

Compound 10.0 (+ -isomer) was prepared from Compound 7.0 (Example 9) by a similar procedure to that described in Examples 2, 4 and 6. Yield 46%, mp 131.6 ° C.

Example 13

Step A:

101

To the compound of Formula 28.0 (Example 8) (0.51 g, 0.85 mmol) and triethylamine (0.18 mL, 1.3 mmol) dissolved in anhydrous dichloromethane (50 mL) was added ClCH ₂ C (O) Cl ( chloroacetyl chloride) (0.28 g, 1.2 eq.), dissolved in dichloromethane (10 mL) at 0 ° C. After stirring for 1.5 hours, 1 M HCl was added and the mixture was shaken. The organic phase was separated and washed with 1 N aqueous NaOH, then brine and dried over anhydrous MgSO 4. Filtration and concentration in vacuo gave the compound of formula 31.0 (0.58 g, 100%, mp 124-134.5 ° C).

Step B:

(31.0)

Compound 31.0 (0.12 g, 0.18 mmol), morpholine (5 mL) and anhydrous sodium carbonate (0.038 g, 2 eq) were stirred overnight at 130 ° C. After concentration in vacuo, the residue was diluted with dichloromethane, washed with water, and dried over anhydrous MgSO 4. Filtration and concentration in vacuo gave a yellow residue (0.17 g), which was purified by thin layer preparative chromatography (silica gel) using 5% methanol-dichloromethane and concentrated ammonium hydroxide to give 13.0 (0.096 g, 75%, temperature). mp 116.6 ° C).

(31.0)

102

Compound of Formula 31.0 (Example 13) (0.12 g, 0.18 mmol), anhydrous dimethylformamide (10 mL), imidazole (0.037 g, 0.54 mmol), and anhydrous sodium carbonate (0.057 g, 0.54 mmol) were added. they were stirred at 130 ° C overnight. The mixture was then cooled to room temperature, filtered and the solids were washed with water. The solids were dissolved in dichloromethane, washed with water and then with 1 N aqueous NaOH. The organic phase was separated, dried over anhydrous MgSO 4, filtered and concentrated in vacuo to give a solid (0.084 g) from which purification by thin layer preparative chromatography (silica gel) using 5% methanol-dichloromethane and concentrated ammonium hydroxide gave the compound of formula 14.0 (0.06 g, 48%, mp 148.9 ° C).

The compound of formula 28.0 (Example 8) (0.21 g, 0.34 mmol) dissolved in anhydrous dichloromethane (10 mL) was added to a dichloromethane solution (10 mL) of oxalyl chloride (1.0 mL) and pyridine (0.08 mL, 3 eq) at 0 ° C. After stirring the resulting solution for 5 minutes, concentrated ammonium hydroxide was added and the mixture was allowed to stand overnight. Then, it was diluted with dichloromethane, water and shaken. The organic phase was separated and washed with brine, 1 M HCl, 1 N aqueous NaOH and again with brine. The organic phase was separated and dried with anhydrous MgSO 4. Filtration and concentration

103 under vacuum afforded a solid (0.17 g), which was purified by preparative thin layer chromatography (silica gel) using 5% methanol-dichloromethane and concentrated ammonium hydroxide to afford 15.0 (0.086 g, 37%, mp 152) , 8 ° C).

To the compound of Formula 16.0 (Example 2) (0.10 g) dissolved in anhydrous dichloromethane (10 mL) was added triethylamine (0.032 mL, 1.5 eq) and methanesulfonyl chloride (0.014, 1.2 eq). The resulting mixture was stirred overnight at room temperature. The solution was diluted with dichloromethane and washed with 1 M HCl, then 1 M aqueous NaOH. The organic phase was separated and dried over MgSO 4 by filtration and concentration in vacuo to give the compound of formula 11.0 (0.099 g, 89%, mp 116 ° C).

Example 17

104

To a compound of Formula 16.0 (Example 2) (0.07 g) dissolved in anhydrous dichloromethane (10 mL) was added triethylamine (0.022 mL, 1.5 eq) and benzoyl chloride (θ ', 014 mL, 1.2 eq) . The resulting mixture was stirred overnight at room temperature. The solution was diluted with dichloromethane and washed with 1 M HCl, then 1 M aqueous NaOH. The organic phase was separated and dried over anhydrous MgSO 4, filtered and concentrated in vacuo to give 12.0 (0.066 g, 85%, mp 117.2 ° C).

Example 18

OCH 3 ^{H C} 'N ^^ _{CH3 0} __

Dissolve 2 g of methyl 3- (dimethylamino) propionate (15 mmol) in 20 mL of EtOH and then add 20 mL of 1 M LiOH. The mixture was stirred at room temperature for 16 hours, then the solvent was removed. The resulting material was dissolved in water and then adjusted to pH 6. The reaction mixture was concentrated to give the product. Mass Spectrum: MH + = 118.

Example 19 (+) -4- (3,10-Dibromo-8-chloro-6,11-dihydro-5H-benzo [5,6] cyclohepta (1,2-b) pyridin-11-yl) -1- [4- (dimethylamino) -1-oxobutyl] -4-piperidinyl] acetyl] -piperidine

105

0.1 g (0.23 mmol) of the product of Example 8 is dissolved in

4- (dimethylamino) butyric selines, 0.04 g (0.22 mmol) DEC, 0.03 (0.22 mmol) HOBT and 0.1 mL N-methyl morpholine at 0-4 ° C. The reaction mixture was stirred overnight and allowed to warm to room temperature. Remove all volatiles and partition between H ₂ O and CH ₂ Cl ₂ . The aqueous phase is extracted with CH ₂ Cl ₂ , the CH ₂ Cl ₂ fractions are combined and dried over MgSO ₄ and concentrated. Purify by flash chromatography, eluting first with 5% MeOH- (NH ₃ ) -CH ₂ Cl ₂ and then 10% MeOH- (NH ₃ ) CH ₂ Cl ₂ to give the compound of formula 12.2. Mass Spec. MH ⁺ = 709, Mp = 69-71 ° C.

Example 20 (+) - 4- (3,10-Dibromo-8-chloro-6,11-dihydro-5H-benzo [5,6] cyclohepta [1,2-b] pyridin-11-yl) -1- (4- (dimethylamino) -1-oxopropyl] -4-piperidinyl] acetyl] -piperidine

The compound of formula 12.3 was prepared by the same procedure described in Example 19 above, but instead

106 of 4- (dimethylamino) butyric acid hydrochloride used 3- (dimethylamino) propionic acid. FAB-MS-MH + = 695, mp = 82-84 ° C.

Example 21 (+) -4- (3,10-Dibromo-8-chloro-6,11-dihydro-5H-benzo [5,6] cycloheptafl, 2-b] pyridin-11-yl) -1- [4] - (diethylamino) -1-oxoethyl] -4-piperidinyl] acetyl] -piperidine

The compound of formula 12.1 was prepared by the same procedure described in Example 19 above, but Ν, Ν-dimethylglycine was used in place of 4- (dimethylamino) butyric acid hydrochloride. FAB-MS-MH + = 681, mp = 123-124 ° C.

Example 22 (+) -4- (3,10-Dibromo-8-chloro-6,11-dihydro-5H-benzo [5,6] cyclohepta [1,2-b] pyridin-11-yl) -1- [4- (piperidinyl) -1-oxoethyl] -4-piperidinyl] acetyl] -piperidine

107

The compound of formula 14.2 was prepared according to the same procedure described in Example 19 above, but using 1-piperidinepropionic acid instead of 4- (dimethylamino) butyric acid hydrochloride. FAB-MS-MH ⁺ = 735, m.p. = 127-128 ^e C.

Example 23 (+) - 4- (3,10-Dibromo-8-chloro-6,11-dihydro-5H-benzo [5,6] cyclohepta [1,2-b] pyridin-11-yl) -1- [4- (tetrahydro-2H-1,4-thiazin-4-yl) -1-oxoethyl-11-dioxide] -4-piperidinyl] acetyl] -piperidine

The compound of formula 14.1 was prepared by the same procedure described in Example 19 above, but thiomorpholine S-dioxidacetic acid was used in place of 4- (dimethylamino) butyric acid hydrochloride. Melting point = 140

- 141 ° C.

Example 24 (+) - Methyl-4- [2- [4 - [(3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo [5,6] cyclohepta [1,2-b] pyridin-11-yl) -1-piperidinyl] -2-oxoethyl] -delta-oxo-1-piperidine pentanoate

108

The compound of formula 15.1 was prepared by the same procedure described in Example 19 above, but monomethylglutarate was used in place of 4- (dimethylamino) butyric acid hydrochloride. FAB-MS-MH ⁺ = 724, mp = 101-102 ° C.

Example 25 (+) -methyl-4- [2- [4 - [(3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo [5,6] cyclohepta [1,2-b] pyridin-11-yl) -1-piperidinyl] -2-oxoethyl] gamma-oxo-1-piperidine butanoate

The compound of formula 15.2 was prepared by the same procedure described in Example 19 above, but monomethylsuccinate was used in place of 4- (dimethylamino) butyric acid hydrochloride. FAB-MS-MH + = 710, mp = 114-115 ° C.

Example 26 (+) -ethyl-4- [2- [4 - [(3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo [5,6] cyclohepta [1,2-b] pyridin-11-yl) -1-piperidinyl] -2-oxoethyl] -beta-oxo-1-piperidine butanoate

109

The compound of formula 15.3 was prepared by the same procedure described in Example 19 above, but monoethyl malonate was used in place of 4- (dimethylamino) butyric acid hydrochloride. FAB-MS-MH + = 710, mp = 77-78 ° C.

Dissolve the (+) product of Step D, Example 8 (0.01 g, 0.017 mmol) in 0.5 mL DMF and stir at room temperature, then add 0.003 g (0.017 mmol) DEC, 0.002 g (0.017 mmol) HOBT and 0.003 g (0.017 mmol) of the product of Example 12. The mixture was stirred at room temperature for 18 hours, then concentrated in vacuo and the residue partitioned between ethyl acetate and water. The organic phase is washed with aqueous sodium carbonate solution, then with brine, dried over MgSO 4, filtered and concentrated in vacuo. The residue is chromatographed on silica gel, eluting with dichloromethane (saturated with ammonia) / methanol (95%: 5%) to give the product (0.01 g) as a white solid, mp 84-90 ° C, mass spectrum MH ⁺ = 709.

Examples 28 to 60

110

The procedure described in Example 27 above was followed, but instead of the product of Example 12, the acids of Table 1 were used to give compounds of Formula 1.7.

where W is as defined in Table 1. The formula number of the compound synthesized is shown in brackets after the W substituent.

Table no

Pr. acid w mp (° C) 28 , Χ · Ο o r '^ so. (6.0-B) 140- 140.8 29 Λ-q (7.0-B) 127.2- 127.7

111

Table 1 - continued

Pr. acid W 1.1. (° C) 30 H OO _λλ οει (8,0-B) 77.2- 78.1 31 O OAc O OEt H OAc 0 Xaa _0E1 (16.0-B) 103.5- 106.4 32 O H Preparative Ex. 4 O H (22.0-B) 129 d 33 Ch .ch ₃ ³ ch ₃ Preparative Ex. 3 O A / vV ³ ch ₃ (23.0-B) 75 34 Ή OH Ϋ O. n o V M OH (24.0-B) 145.8- 147.7 35 "Ax? (30.0-B) 125.8- 127.3 36 o ch ₃ ho ^x ^ Y ' ⁿ ' ch ₃ o O ch ₃ v · ». O (33.0-B) 95-143 37 about · OH HO ABOUT (37.0-B)

112

Table 1 - continued

Pr. acid w t .t. (° C) 38 ABOUT .CN HO x x kx ^CN (44.0-B) 124- 125 39 O ^Χ ^ γ ^Ν 'θΟΗ ₃ O IN·,., ABOUT (49.0-B) 204.5 40 OO XX ho ^x ^^ ^x ^ nh ₂ OO AA _NH! (50.0-B) 137.4- 138 41 oo HO ^X ^ ^X - ^X ^ N OCH ₃ i ^J H oo ^^ Xoch ₃ (51.0-B) 115.8- 116.4 42 o ch ₃ ^HO p ^N h ₃ c o ch ₃ h ₂ c (65.0-B) 43 oo HO 2 (CH ₂ ) ₅ Q ^{C 3} oo JL JL .ch, ^ Ych ₂ ) ₅ ^^ o (68.0-B) 44 About Ho-Uy ™ ³ O About YyC « ₃ O (72.0-B) 113- 120 45 xo RJO (75.0-B) 95-100

113

Table 1 - continued

Pr. acid W t .t. (° C) 46 About OEt U 1 HO ^ - ^ OEt O OEl ΛΛ. (76.0-B) 100- 108 47 ABOUT About HN * \ 0 0 0 HN \ aJ \ ^nh 0 (77.0-A) 192- 203 48 ABOUT about h <A> / about AJY about (79.0-B) 172- 190 49 about IN? about (81.0-B) 154- 163 50 "αΛ JUQ (82.0-B) 129- 139 51 about F, J. Med. Chem. (1993) 3S. 2300 ME TOO (85.0-B) 114.5- 119.3 52 with ° LK SE-H ⁰ (86.0-B) 87-88 53 o ^H o / Λζ ^ ^Ν Υ> HO θ 1 o ^H O / o (89.0-B) 102.7- 103.3

114

Table 1 - continued

Pr. acid W 1.1. (° C) 54 ^{η <λ} λ5ο Preparative Ex. 5 0 H (95.0-B) 145 d 55 Tetrahedron (1989) .45. 69 (114.2-B 129- 143 56 Tetrahedron (1989) 45, 69 xX> (114.3-B) 124- 132 57 "•• X Tetrahedron (1989). 45. 69 XX? (114.4-B) 127- 136 58 och ₃ Äx ^ r ° and ₃ (101.0-B) 74-75 59 o, and ₃ ^H ° F o ABOUT ABOUT (104.0-B) 60 about 1. ° ** ABOUT ABOUT (105.0-B) 114- 115 61 oo Ϊ U OCH ₂ CH ₃ 0 O * U ϊ _{2 2} ch ₃ (106.0-B) 101.1- 101.5

Press

Example 62

Dissolve (+) the product of Step D, Example 8 (0.744 g, 1.25 mmol) in 20 mL of dichloromethane containing 0.348 mL (2.5 mmol) of triethylamine, stir at room temperature, then add 0.1 ml (1.26 mmol) of chloroacetyl chloride. The mixture was stirred for 10 hours and then 20 mL of 1 N HCl was added. The organic solvent layer was washed with aqueous sodium carbonate solution, dried over MgSO 4 and concentrated in vacuo to give 0.71 g of product.

Step B

116

Dissolve 0.120 g (0.78 mmol) of the product of Step A, 0.0365 g (0.535 mmol) of 4-methylimidazole and 0.057 g (0.535 mmol) of sodium carbonate in 10 mL of DMF and stir at 120-130 for 18 h. ° C, then cooled to 25 ° C, 30 ml of water are added and the precipitated solid is filtered. The solid was dissolved in 50 mL of dichloromethane and washed with 1 N NaOH. The organic layer was dried over MgSO 4 and concentrated in vacuo, and the residue was chromatographed on silica gel TLC using methanol: dichloromethane saturated with ammonia (5:95) to give 0.06 g of the product as a white solid, m.p. 148.9 ° C. .

Examples 63 to 75

Following the procedure of Example 62 except that the amine listed in Table 2 was used instead of 4-methylimidazole, compounds of formula 1.7 were obtained.

of substituents.

of formula

W subTable 2

Pr. 1 J amine W « 1.1. (° C) 63 H ' ^N yN ch ₃ ch ₂ (10.0-B) 137.8

117

Table 2 - continued

Pr. amine w '1.1. (° C1 64 Q H • P 151.3 65 P H XS (13.0-B) 154.2 66 ph P "LR H F ph o μ (20.0-B) 150.3 (D) 67 no ₂ -p H No ₂ (26.0-B) 168.1 68 h'o XO (34.0-B) 123.4 69 H '\ p CO ₂ CII ₃ ΧΧ CO ₂ CH ₃ (35.0-B) 184- 190 70 H ₂ CO ₂ CH ₂ Ph XQ Co ₂ n (52.0-B) 178.6 71 ^N Xj = -CH 3 (IjEl _x ^ JL ~ ^N XJA _{CH3 CO2} El (53.0-B) 156.1

118

Table 2 - continued

Pr. amine W mp (° C) 72 _H ' ^N x ^^ * co ₂ Et ch ₃ 0 ^ = N xA ^ N ^^ - cOaEl ch ₃ (54.0-A) 158.7 73 CO ₂ CH ₂ Ph 9 Χφ CO ₂ CH ₂ Ph (55.0-B) 130.4 74 , —N O o ΓΛ N ^N OCH ₃ (56.0-B) 122.8 75 N = \ N from ^N Na ^ · ^ ON = r \ a> ⁿ (57.0-B) 125.3

Example 76

119

Dissolve 1 equivalent of the product of Example 59 (compound 104.0-B, Table 1) in methanol containing 1.2 equivalents of 1 N KOH in methanol and stir at 25 ° C for 48 hours, then acidify with 1 N HCl to pH 2 and extracted with dichloromethane. The organic layer was dried over MgSO 4 and concentrated in vacuo. The residue was purified by preparative silica gel TLC using methanol / dichloromethane / acetic acid (5: 94: 1) to give the product as a white solid, mp 240.1 ° C.

Example 77

Dissolve 1 equivalent of the product of Example 30 (Compound 8.0-B, Table 1) in 95% aqueous ethanol containing 1.1 equivalents of LiOH and stir at 25 ° C for 16 hours. Concentrate in vacuo to give the product as a white solid. in the form of a white solid.

Example 78

120

Following the procedure of Example 77, instead of the product of Example 59 (compound 104.0-B, Table 1), the product of Example 60 (compound 105.0-B, Table 1) was used to give the product as a white solid.

Example 79

Following the procedure of Example 77, instead of the product of Example 59 (compound 104.0-B, Table 1), the product of Example 61 (compound 106.0-B, Table 1) was used to give the product as a white solid.

Dissolve 1 equivalent of the product of Example 43 (Compound 68.0-B, Table 1) in 95% aqueous methanol containing 1.1 equivalents of NaOH and stir at 25 ° C for 16 hours, then concentrate in vacuo to afford the title compound. m.p. 215.6-216.2 ° C.

Example 81

Dissolving 1 equivalent of the product of Example 58 (compound 101.0-B, Table 1) in 95% aqueous methanol containing 1.1 equivalents of NaOH, stirring for 16 hours at 25 ° C, concentrating in vacuo to give the product as a white solid at mp 240 ° C (d).

Example 82

br

Dissolve 1 equivalent of the product of Example 81 (compound 107.0; - B) in DMF containing 5.0 equivalents of ammonium chloride and 1 equivalent of DEC, HOBT and N-methylmorpholine. The mixture was stirred at room temperature for 18 hours, then concentrated in vacuo and the residue partitioned between ethyl acetate and ethyl acetate.

122, the organic phase is washed with aqueous sodium carbonate solution, brine and then dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was chromatographed (silica gel) to give the product as a white solid, mp 125.5-126.5 ° C.

Example 83

Dissolve 1 equivalent of the product of Example 78 (compound 18.0-B) in DMF containing 5.0 equivalents of ammonium chloride and 1 equivalent of DEC, HOBT and N-methylmorpholine. The mixture was stirred at room temperature for 18 hours, then concentrated in vacuo and the residue partitioned between ethyl acetate and water, the organic phase was washed with aqueous sodium carbonate solution, brine and then dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was chromatographed on silica gel to give the product as a white solid, mp 142.8-143.3 ° C.

Example 84

123

Dissolve 1 equivalent of the product of Example 80 (compound 70.0-B) in DMF containing 5.0 equivalents of ammonium chloride and 1 equivalent of DEC, HOBT and N-methylmorpholine. The mixture was stirred for 18 hours at room temperature, then concentrated in vacuo and the residue partitioned between ethyl acetate and water, the organic phase was washed with aqueous sodium carbonate, brine and then dried over _MgSO4, filtered and concentrated in vacuo. The resulting residue was chromatographed on silica gel to give the product as a white solid, mp 119.2-120 ° C.

Example 85

Dissolve 1 equivalent of the product of Example 81 (compound 107.0-B) in DMF containing 5.0 equivalents of ammonium chloride and 1 equivalent of DEC, HOBT and N-methylmorpholine. The mixture was stirred for 18 hours at room temperature, then concentrated in vacuo and the residue partitioned between ethyl acetate and water, the organic phase was washed with aqueous sodium carbonate, brine and then dried over _MgSO4, filtered and concentrated in vacuo. The resulting residue is chromatographed on silica gel to give the product in the form

I

I white solid.

Example 86

124

Dissolve 1 equivalent of the product of Example 79 (compound 19.0-B) in DMF containing 5.0 equivalents of ammonium chloride and 1 equivalent of DEC, HOBT and N-methylmorpholine. The mixture was stirred at room temperature for 18 hours, then concentrated in vacuo and the residue partitioned between ethyl acetate and water, the organic phase was washed with aqueous sodium carbonate solution, brine, then dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was chromatographed on silica gel to give the product as a white solid.

Example 87

Dissolve 1 equivalent of the product of Example 59 (compound 104.0-B, Table 1) in dichloromethane containing 4.0 equivalents of anhydrous hydrazine, stir the mixture for 48 hours, then concentrate in vacuo to a residue which is subjected to preperative TLC on silica gel using methanol / dichloromethane (5:95) to give the product as a yellow solid, mp 90 ° C.

125

Example 88

Dissolve 1 equivalent of the product of Example 59 (compound 104.0-B, Table 1) in methanol containing 1.4 equivalents of LiOH, stir for 18 hours, then add DMF containing 1 equivalent of DEC, HOBT, N-methylmorpholine and O tert-butyldimethylsilylhydroxylamine. The mixture was stirred at room temperature for 48 hours, then concentrated in vacuo and the residue partitioned between ethyl acetate and water. The organic phase was dried over MgSO ₄ , filtered and chromatographed on silica gel using methanol / dichloromethane (5:95) to give the product as a white solid, mp 103.0 ° C.

Example 89

Dissolve 1 equivalent of the product of Example 59 (compound 104.0-B, Table 1) in methanol containing 3.0 equivalents of KOH and 3.0 equivalents of glycine tert-butyl ester, the mixture is stirred for 7 days, then concentrated in vacuo to a residue. is chromatographed on silica gel using

126 methanol / dichloromethane (5 as a yellow solid: 95) to give the product m.p. 108.0 ° C.

Dissolve 1 equivalent of the product of Example 59 (compound 104.0-B, Table 1) in methanol containing 3.0 equivalents of KOH and 3.0 equivalents of O-benzylhydroxylamine hydrochloride, stirred for 48 hours, then concentrated in vacuo and the residue concentrated in vacuo. Chromatography on silica gel using methanol / dichloromethane / acetic acid (10: 89,5: 0,5),

to give a yellow melting product of 75.0 ° C. solid with temperature Example 91 br · Cl (64.0-B) NT br about II H ' ^N ' ch ₃ ABOUT* K / k / J o

Dissolve 1 equivalent of the product of Example 59 (compound 104.0-B, Table 1) in methanol containing 4.0 eq methylamine equivalents and stir the mixture for 18 hours, then concentrate in vacuo and chromatograph the residue on silica gel using methanol / dichloromethane saturated ammonia (5:95) to give the product as a yellow solid, mp 86-132 ° C.

Example 92

Dissolve 1 equivalent of the product of Example 52 (Compound 86.0-B, Table 1) in dichloromethane containing 2.0 equivalents of trifluoroacetic acid and stir for 2 hours, then concentrate in vacuo and partition the residue between dichloromethane and aqueous sodium carbonate . The organic layer was dried over MgSO ₄ , concentrated in vacuo to give the product as a white solid, mp 120.6-120.8 ° C.

Example 93

128

Dissolve 1 equivalent of the product of Example 53 (compound 89.0-B, Table 1) in dichloromethane containing 2.0 equivalents of trifluoroacetic acid and stir for 2 hours, then concentrate in vacuo and partition the residue between dichloromethane and aqueous sodium carbonate . The organic layer was dried over MgSO ₄ , concentrated in vacuo to give the product as a white solid, mp 114-115 ° C.

Example 94

Dissolve 1 equivalent of the product of Example 1 in dichloromethane containing 2.0 equivalents of trifluoroacetic acid and stir for 2 hours, then concentrate in vacuo and partition the residue between dichloromethane and aqueous sodium carbonate. The organic layer was dried over MgSO ₄ , concentrated in vacuo. Then the residue was dissolved in dichloromethane containing 1.5 equivalents of triethylamine and 1.2 equivalents of dimethylsulfamoyl chloride, stirred for 18 hours and then washed with 1 N HCl and then 1 N NaOH. The organic layer was dried over MgSO ₄ and concentrated in vacuo to give the product, mp 124.4-130 ° C.

Example 95

br

(39.0-B)

H i

ⁿ x _s ^ nh ₂ ° 2

129

Dissolve 1 equivalent of the product of Example 1 in dichloromethane containing 2.0 equivalents of trifluoroacetic acid and stir for 2 hours, then concentrate in vacuo and partition the residue between dichloromethane and aqueous sodium carbonate. The organic layer was dried over MgSO ₄ and concentrated in vacuo. The residue was then dissolved in 10.0 equivalents of aqueous sulfamide and refluxed for 48 hours. Concentrate in vacuo and chromatograph the residue on silica gel using methanol / dichloromethane saturated with ammonia (5:95) to give the product, m.p. 151.9 ° C.

Example 96

The product of Example 31 (Compound 16.0-B, Table 1) (372.1 mg, 0.468 mmol) was dissolved in 3 mL of 6 M HCl and the solution was stirred at room temperature overnight, then 25 mL of water was added to the reaction mixture. the resulting product was filtered and washed with 0.1 M HCl. The filtrate was saturated with NaCl and extracted continuously for 48 hours to give additional crude product. The combined crude product fractions were purified by flash chromatography (C-18 reverse phase silica, gradient 50% MeOH / 0.17 M HOAc to 90% MeOH / 0.17 M HOAc). The resulting material was dissolved in MeOH and added to water. The resulting suspension was evaporated to dryness to give the title compound as a white solid

130 (mp 133.5-141.2 ° C, heating 2-3 ° C / min).

Example 97

The product of Example 34 (compound 24.0-B, Table 1) (450.0 mg, 0.56 mmol) was dissolved in 20 mL of CH 2 Cl 2, cooled to 0 ° C, and then 8 mL of trifluoroacetic acid was added slowly. After an hour, the cold mixture was diluted with 50% aqueous NaOH and water. The mixture was extracted with CH ₂ Cl ₂ , the extract was dried over MgSO ₄ and evaporated to give the title product as a yellow solid (230 mg, mp 161-163.0 ° C).

Example 98

The product of Example 96 (compound 74.0-B) (93.6 mg,

0.129 mmol) and 1-hydroxybenzotriazole (27.3 mg, 0.202 mmol) are dissolved in 1 mL DMF, then NH ₄ Cl (14.8 mg,

131

0.276 mmol), N-methylmorpholine (70 microliters) and DEC.HCl (30.8 mg, 0.161 mmol). The mixture was evaporated after 4 hours and the residue was purified by flash chromatography (C-18 reverse phase silica, gradient 50% MeOH / 0.17 M HOAc to 90% MeOH / 0.17 M HOAc). The resulting material was lyophilized from HOAc / H ₂ O to give the title compound as a brown solid (67.7 mg, mp 115.2-122.0 ° C, heating 2-3 ° C / min).

Example 99

(1O9.O-B)

Dissolve 1 equivalent of the product of Example 77 (compound 14.0-B) in DMF containing 1.0 equivalent each of DEC, HOBT, N-methylmorpholine and pyrrolidine. The mixture was stirred at room temperature for 18 hours, then concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic phase is washed with aqueous sodium carbonate solution and then with brine. The organic phase is dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting residue was chromatographed on silica gel to give the product as a white solid.

Example 100

Cl (110.0-A)

br

132

Dissolve 1 equivalent of the product of Example 77 (compound 14.0-B) in DMF containing 1.0 equivalent each of DEC, HOBT, N-methylmorpholine and piperidine. The mixture was stirred at room temperature for 18 hours, then concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic phase is washed with aqueous sodium carbonate solution and then with brine. The organic phase is dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting residue was chromatographed on silica gel to give the product as a white solid, mp 135-136 ° C.

Example 101

Dissolve 1 equivalent of the product of Example 77 (compound 14.0-B) in DMF containing 1.0 equivalent each of DEC, HOBT, N-methylmorpholine and morpholine. The mixture was stirred at room temperature for 18 hours, then concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic phase is washed with aqueous sodium carbonate solution and then with brine. The organic phase is dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting residue was chromatographed on silica gel to give the product as a white solid, mp 135-136 ° C.

Example 102

O O (112.0-A)

- ^ch 3

CH,

133

Dissolve 1 equivalent of the product of Example 77 (compound 14.0-B) in DMF containing 1.0 equivalent each of DEC, HOBT, N-methylmorpholine and dimethylamine. The mixture was stirred at room temperature for 18 hours, then concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic phase is washed with aqueous sodium carbonate solution and then with brine. The organic phase is dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting residue was chromatographed on silica gel to give the product as a white solid, mp 133-134 ° C.

tests:

FPT IC ₅₀ (farnesyl protein transferase inhibition, in vitro enzyme assay) and COS Cell IC ₅₀ (Cell-Based Assay) were determined according to the procedures published in WO 95/10516, published April 20, 1995. GGPT IC50 (geranyl geranyl protein transferase inhibition) , in vitro enzyme assays), Cell Mat Assay assays, and antitumor activity (in vivo antitumor studies) can be determined by the assays described in WO 95/10516. WO 95/10516 is incorporated herein by reference.

Further assays can be performed using essentially the same procedures as described above, but the T24-BAG cells are replaced with an alternative tumor cell line. The assay can be performed with DLD-1-BAG human intestinal tumor cells expressing the activated K-ras gene. The activity of the compounds of the invention against other types of cancer cells can be demonstrated using other cancer cell lines known in the art.

134

Soft Agar Assay:

The embedded independent propagation is characteristic of tumorigenic cell lines. Human tumor cells were resuspended in growth medium containing 0.3% agarose and a certain concentration of farnesyl transferase inhibitor was used. The solution was applied to growth medium solidified with 0.6% agarose containing the same concentration of farnesyl transferase inhibitor as the top layer. After the top layer solidified, the plates were incubated for 10-16 days at 37 ° C in the presence of 5% CO ₂ to grow the colony. After incubation, colonies were stained by overlaying agar with a solution of MTT (3- [4,5-dimethylthiazol-2-yl] -2,5-diphenyltetrazolium bromide, thiazolyl blue) (1 mg / ml in PBS). Colonies were counted and IC 50 was determined.

Compounds 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0,

10.0, 11.0, 12.0 12.1, 12.2, 12.3, 13.0, 14.1, 14. 2, 15.1, 15.2, 15.3 17.0-A, 18.0-A, 23.0-A, 79.0-A, 104.0-B, 108.0-B had FPT nanomolar). IC 50 (H-ras) ranging from <2 to 31.7 nM (na- Compounds 6. 0, 7.0, 8.0, 10.0, 11.0, 12.0, 12. 1, 12.3, 13.0, 14.1 and 14.2 , 15.1, 15.2 and 15.3 had a Cos Cell IC50 in the range of 10 to 700 nM. Compounds 6. 0-A, 7.0-A, 8.0-A, 9.0-A, 10.0-A, 11.0-B, 12.0-A, 13.0-A, 14.0-A, 16.0-A, 17.0-A, 18.0-A, 19.0-B, 20.0-A, 21.0-A, 22.0-A, 23.0-A, 24.0-A, 26.0-A, 30.0-B, 32.0-B 34.0-A, 35.0-A, 37.0-A, 38.0-A, 39.0-B, 44.0-B 50.0-A, 51.0-A, 52.0-A, 53.0-A, 54.0-B, 55.0-B 57.0-A, 58.0-A, 59.0-A, 60.0-A, 63.0-B, 64.0-B 68.0-A, 69.0-A, 70.0-A, 71.0-A, 72.0-B, 74.0-B 76.0-A, 77.0-A, 79.0-A, 81.0-A, 82.0-B, 85.0-B 88.0-B, 90.0-B, 89.0-B, 92.0-B, 95.0-B, 101.0-B 114.0-B, 114.2-B, 114.3-B and 114.4 -B, they should FPT IC ₅ in range 0.7 to 18 nM.

135

Compounds 2 ; .o, 3.0, 4.0, 6.0, 7.0 8.0, 9.0 , 10.0, 12.1, 12.3, 16. 0, 6.0-B 7.0-B, 9.0-B 10.0-B, 11.0-B, 12.0-B, 13.0-B, 17.0-B and 18.0-B had FPT IC ₅₀ (K-ras) in the range of 14.5 to 71.2 nM • Compounds 6 .0, 16.0, 17.0, 6.0, 6.0 -B, 7.0-B 9.0-B, 10.0-B, 11.0-B, 12.0-B, 13.0-A, 14.0-A, 16.0-B, 17.0-B, 18.0-B, 19.0-B, 22.0-B, 23.0-B 26.0-B, 30.0-B, 32.0-B, 33.0-B, 34.0-B, 35.0-B 38.0-B, 39.0-B, 44.0-B, 49.0-B, 50.0-B, 51.0-B 53.0-B, 54.0-B, 55.0-B, 56.0-B, 57.0-B, 58.0-B 60.0-B, 63.0-B, 64.0-B, 68.0-B, 69.0-B, 70.0-B 72.0-B, 74.0-B, 75.0-B, 77.0-B, 79.0-B, 81.0-B 85.0-B, 88.0-B, 89.0-B, 92.0-B, 95.0-A, 101.0-A, 104.0-A, 107.0-B 114.0-B, 114.2-B , 114.2-B and 114.4-B had Cos Cell v extent 9 to> 1 000 nM.

compounds 10.0, 12.1, 12.3 15.2, 16.0, 18.0, 6.0-B 9.0-B, 10.0-B, 11.0-B, 12.0-B, 13.0-B, 14.0-B, 16.0-B, 17.0-B, 18.0-B, 19.0-B, 21.0-B, 22.0-B, 23.0-B, 24.0-B, 26.0-B, 30.0-B, 32.0-B, 33.0-B, 34.0-B, 35.0-B, 37.0-B, 38.0-B, 39.0-B, 44.0-B, 49.0-B, 50.0-B, 52.0-B, 53.0-B, 54.0-B, 55.0-B, 56.0-B, 57.0-B, 59.0-B, 60.0-B, 63.0-B, 64.0-B, 68.0-B, 69.0-B, 70.0-B, 71.0-B, 72.0-B, 74.0-B, 75.0-B, 77.0-B, 79.0-B, 81.0-B, 82.0-B, 85.0-B, 88.0-B, 89.0-B, 92.0-B, 95.0-B 104.0-B 114.0-B, 114.2-B, 114.3-B , and 114.4 -B had ' Soft Agar Assay v extent

19.5 to> 500 nM.

Solid or liquid inert, pharmaceutically acceptable carriers can be used to prepare pharmaceutical compositions from the compounds described herein. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories. The powders and tablets may contain 5 to 70% of the active ingredient. Suitable solid carriers are known in the art, for example magnesium carbonate, magnesium stearate,

Talc, sugar, lactose. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.

In the preparation of suppositories, a wax such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active ingredient is dispersed homogeneously therein while stirring. The molten homogeneous mixture is then poured into suitable sized molds, allowed to cool and solidify.

Liquid preparations include solutions, suspensions and emulsions. They may be aqueous or aqueous propylene glycol solutions for parenteral injection.

Liquid form preparations may also contain solutions for intranasal administration.

Aerosol preparations suitable for inhalation may contain solutions and solids in powder form which may be in combination with a pharmaceutically acceptable carrier such as compressed gas.

Also included are solid formulations that are converted, prior to use, to liquid formulations for either oral or parenteral administration. Such liquid forms are solutions, suspensions and emulsions.

The compounds of this invention may be administered transdermally.

The transdermal formulations may be in the form of creams, lotions, aerosols and / or emulsions and may be in a matrix or reservoir transdermal patch, as is commonly used for this purpose.

The compounds are preferably administered orally.

The pharmaceutical preparation is preferably in the form of dosage units. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active ingredient, for example, an effective amount to achieve the desired result.

137

The amount of active ingredient per unit dose of the preparation is adapted or varied from 0.1 mg to 1000 mg, more preferably from 1 mg to 300 mg, according to the method of use.

The actual dosage employed may vary depending upon the requirements of the patient and the severity of the condition being treated. Determining the appropriate dosage for a particular situation is a matter of expert judgment. Generally, treatment is initiated by administration of lower doses that are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until an optimum effect is obtained. If necessary, the total daily dose may be divided and administered in portions throughout the day.

The number and amount of administration of the compounds of this invention and their pharmaceutically acceptable salts are adjusted by the attending physician, taking into account the age, fitness, weight and condition of the patient as well as the severity of the symptoms being treated. A typical recommended dosage regimen for blocking tumor growth is oral administration of 10 to 2000 mg / day, preferably 10 to 1000 mg / day in two or four doses. Compounds administered within this dosage range are nontoxic.

The following examples are examples of pharmaceutical dosage forms containing a compound of the invention. The scope of the invention in terms of the pharmaceutical composition is not limited to these examples.

138

Examples of pharmaceutical dosage forms Example A - tablets

Number ingredients mg / tablet mg / tablet First Active compound 100 500 Second Lactose USP 122 113 Third Maize starch (food) as 10% paste in purified water 30 40 4th Maize starch (Food) 45 40 5th Magnesium stearate 3 7 Together 300 700

Method of preparation

In a suitable mixer, components # 1 and 2 are mixed for 10-15 minutes. The mixture is granulated with component # 3. If desired, the moistened granules are passed through a coarse sieve (e.g. 1/4 '', 0.63 cm). The wet granules are dried. If necessary, dry granules are sieved, blended with component # 4 and blended for 10-15 minutes. Add component 5 and mix for 1 to 3 minutes. The mixture is compressed on a suitable tableting machine to the appropriate size and weight.

Example B - Capsules

Number ingredients mg / capsule mg / capsule First Active compound 100 500 Second Lactose USP 106 123 Third Maize starch (Food) 40 70 4th Magnesium stearate NF 7 7 Together 253 700

139

Method of preparation

In a suitable mixer, components # 1, 2 and 3 are mixed for 10-15 minutes. Component # 4 is added and mixed for 1 to 3 minutes. The mixture is filled in a suitable capsule device into two-piece hard gelatin capsules.

While the present invention has been described in connection with the specific embodiments set forth above, other alternatives, modifications and variations will be apparent to those skilled in the art. All such alternatives, modifications and variations are within the scope of this invention.

Industrial use:

The novel compounds prepared by the method of the present invention have the ability to inhibit the enzyme farnesyl protein transferase, and can be used to inhibit abnormal cell growth and thus to treat certain cancers.

Claims (18)

1 selected from the group: 150 151 152 153 Ο 154 155 156 157 158 159 160 161 162 t «· 163 164 165 CO ₂ H 166 167 168 169 170 171 172 173 or a pharmaceutically acceptable salt or solvate thereof. (1) z is 1, 2, 3, 4 or 5; (1) z is 0; (1) v is 1 or 2; (1) v is 0; (1) s is 1, 2, 3, 4 or 5; and (2) R ¹³ is selected from the group consisting of: (a) H and -C (O) OR ¹⁶ , wherein R ¹⁶ is alkyl; (1) r is 1 or 2; (1) r is 0; (1, —ON = C ^Z CH, CH, OAc I ABOUT II (2) - C - C - C - OC ₂ H ₅ H Ho ⁵ (3) - O - N - C 143 (4) -H (5) -ch (and ₂ ch ₃ ) ₂ ; 1. Compound of formula * \ HH, or a pharmaceutically acceptable salt or solvate thereof, wherein: one of a, b, c and d is N or NR ⁹ wherein R ⁹ is O ", CH ₃ or - (CH ₂ ) _n CO ₂ H, wherein n is 1 to 1 3, and the remaining a, b, c, and d groups represent CR ¹ or CR ² ; or each of a, b, c and d is independently selected from CR ¹ or CR ² ; each R ¹ and each R ² is independently selected from the group consisting of H, halogen, -CF 3, -OR ¹⁰ , -COR ¹⁰ , -SR ¹⁰ , -SIL ² R ¹¹ (where t is 0, 1 or 2), -SCN, -N (R ¹⁰⁾ 2, -NR ^{1 O U} R, -NO 2, -OC (O) R ^10, -CQzR ^10, -OCO2R ^n, -CN, -NHC (O) R ^10, -NHSO 2 R ^10, -CONHR ^10, -CONHCH2CH ₂ OH, -NR ¹⁰ COOR ^n, -SR ¹¹ C (O) OR ¹¹ , -SR ¹¹ N (R ¹⁵ ) 2, wherein each R ¹⁵ is independently selected from H and -C (O) OR ¹¹ , benzotriazol-1-yloxy, tetrazol-5-ylthio, or substituted tetrazol-5-ylthio, alkynyl, alkenyl or alkyl, said alkyl or alkenyl group may preferably be substituted with halogen, -OR ¹⁰ or -CO ² R ¹⁰ ; 141 R ³ and R ⁴ are the same or different, and each independently represents H, which of the substituents R ¹ and R ² or R ³ and R ⁴ together represent a saturated or unsaturated C 5 -C 8 alkyl group; a ring fused to a benzene ring (ring III); R ^5, R ^6, R ⁷ and R ⁸ independently represent H, -CF3, ^-COR10, alkyl or aryl, said alkyl or aryl optionally being substituted with -OR ^10, -SR ^10, -S (O) t ^R, -NR ¹⁰ COOR ^n, N (R ¹⁰⁾ 2, -NO 2, -COR ^10, -OCOR ^10, -OCO2R ^11, -CO 2 R ^10, -OPO3R ^10, or R ⁵ is combined with R ⁶ to represent = 0 or = S and / or is R ⁷ is combined with R ⁸ , and is = O or = S R ¹⁰ represents H, alkyl, aryl or aralkyl; R ¹¹ represents alkyl or aryl; X represents N, CH or C, wherein C may preferably contain a double bond (shown by the dotted line) connecting its atom to carbon atom 11; the dotted line between carbon atoms 5 and 6 represents a double bond is preferably such, when a double bond is present, A and B independently represent -R ^10, halo, -OR ^11, -OCO2R ^n, and OC (O) R ^10, and where there is no double bond between carbon atoms 5 and 6, each A and B group is independently H, - (OR ¹¹ ) 2, H and halogen, dihalogen, alkyl and H, (alkyl) 2, -H, and - OC (O) R ¹⁰ , H and -OR ¹⁰ , = O, aryl and H, = NOR ¹⁰ or -O- (CH 2) _p -O-, wherein p is 2, 3 or 4; and W is selected from the group consisting of: (D (2) O H (3) O H (4) ABOUT ABOUT a. -C-C-Ichak rm 142 where: R ¹² is selected from the group consisting of: (a) H; (b) alkyl; (c) aralkyl; and (d) heteroalkyl; . R ¹³ and R ¹⁴ are independently selected from the group consisting of: (a) H; (b) -C (O) OR ¹⁶ wherein R ^{16 is} alkyl, aralkyl and heteroaralkyl; (c) -SO ₂ R ¹⁷ wherein R ¹⁷ is selected from the group consisting of: NH ₂ , -N (alkyl) ₂ wherein each alkyl is the same or different alkyl, aryl, aralkyl, heteroaryl and heteroaralkyl; (d) -C (O) R ¹⁸ wherein R ¹⁸ is selected from the group consisting of aryl, alkyl, aralkyl, heteroaryl and heteroalkyl; (e) C _1-6 alkyl; (f) alkaryl; and (g) C _3-6 cycloalkyl; r is 0, 1 or 2; s is 1, 2, 3, 4, or 5, and each Y for all -CY ₂ groups is independently selected from U and -OH, provided that both Y substituents of each -CY ₂ group are not OH, and provided that: that the alpha -CY ₂ - group to the nitrogen both Y substituents are H, such that the group forms a 3, 4, 5, 6 or 7-membered ring; v is 0, 1 or 2; R ¹⁵ is selected from the group consisting of: a) heteroaryl; (b) a group selected from: (2) R ²² is selected from: -OR ²³ , ONa, -OLi, alkyl, -NR ²⁴ R ^25, or: (2) R ²² is -NR ²⁴ R ²⁵ ; and (3) R ²⁴ and R ²⁵ are independently selected from: -H, -NH ₂ , alkyl, alkoxy, -OH, -CH ₂ CO ₂ H or -OCH ₂ C ₆ H ₅ ; and (G) ABOUT II ABOUT II —C- (CH2 _{) 2} —R ²² where: (2) R ¹² is H; and 147 (3) R ¹⁵ is heterocycloalkyl; (F) OO ¹¹ U 22 —C-CH3 — CR ²² where: (2) R ¹² is H; and (3) R ¹⁵ is selected from the group consisting of: About r ^? ° ’ CO ₂ Et 146 and -OH, -CN; (E) OH II I, -CC- _(CH2 1-RR ¹² wherein: (2) R ¹² is H; (2) R ¹² is selected from the group consisting of: (a) H; (b) alkyl; (c) aralkyl; and (d) heteroaralkyl; and (3) R ¹³ and R ¹⁴ are independently selected from the group consisting of (a) H; (b) C (O) OR ¹⁶ wherein R ¹⁶ is alkyl; (c) -SO ₂ R ¹⁷ wherein R ¹⁷ is alkyl or aryl; (d) -C (O) R ¹⁸ wherein R ¹⁸ is aryl; and (e) alkyl; ^(IB) OH r '3 -U _? (CH _{2, N} - < R ¹² where: A compound according to claim 1, wherein R ² is H; R ¹ is selected from the group consisting of: Br and Cl; R ³ is selected from the group consisting of: Br and Cl; R ⁴ is selected from the group consisting of: H, Br and Cl; R ⁵ , R ⁶ , R ¹ and R ⁸ are H; A and B are both H ₂ and lacking an optional bond between C 5 and C 6. (3) R ²³ is alkyl; and (4) R ²⁴ and R ²⁵ are independently selected from H, -CH (OCH ₃ ) CH (CH ₃ ) 2, or - NO 1; (3) R ¹³ is alkyl and R ¹⁴ is H, alkyl or -C (O) OR ¹⁶ , wherein 145 R ¹⁶ is alkyl; where: (C) O H u i z A compound according to claim 1 or 2, wherein W is selected from the group consisting of: (A) OH _R 13 ^{11 1} -CC- (CH ₂ l _y N 'to 12 wherein: A compound according to any one of claims 1 to 3, wherein R ³⁴ is H. Compound according to any one of claims 1 to 3, characterized in that R ⁴ is selected from the group consisting of: Cl or Br. 148 A compound according to any one of claims 1 to 5, wherein X is CH. (6) -OR ²³ wherein R ²³ is selected from the group consisting of: alkyl, aryl, and H; and (7) -N'R ²⁵ wherein R ²⁴ and R ²⁵ are independently selected from the group consisting of: -NH ₂ , alkoxy, -OH -CH ₂ CO ₂ H, -OCH ₂ Ph, CH (OOfe) CH (Qfe) ₂ , alkyl, aryl, H, aralkyl and heteroaralkyl; or R ²⁴ and R ²⁵ together form a carbon chain with 4 or 5 (CH ₂ , 144 groups) so that R ²⁴ and R ²⁵ together with the nitrogen to which they are attached form a 5- or 6-membered heterocycloalkyl ring. (6) -OH; and (7) -CN; and (c) heterocycloalkyl selected from the group consisting of: z is 0, 1, 2, 3, 4, or 5, wherein each -CH ₂ - group is suitably substituted with -OH; R ²² represents a group selected from: Compound according to any one of claims 1 to 6, characterized in that it contains the groups: wherein R1, R3 and R4 are each independently selected from halogen; and A, B, X and W are as defined in claim 1. A compound according to any one of claims 1 to 7, wherein R ¹ is Br, R ³ is Cl and R ⁴ is Br. A compound according to any one of claims 1 to 8, wherein said compound has the formula: 149 10th A compound according to claim A method of treating cancer cells, comprising administering an effective amount of any of the compounds of claims 1 to 10. ^{11 1} ~ 15 -CC- (CH ₂₎ -R ¹⁵ R ¹² where: Method according to claim 11, characterized by 174 wherein the cells to be treated are pancreatic tumor cells, cancer tissue cells, myeloid leukemia cancer cells, thyroid follicular tumor cells, myelodysplastic tumor cells, epidermal cancer tumor cells, bladder cancer tumor cells, colon tumor cells, mammary tumor cells prostate tumor cancer cells. 13. A method of inhibiting farnesyl protein transferase comprising administering an effective amount of any of the compounds of claims 1 to 10. 14. A pharmaceutical composition comprising an effective amount of any of the compounds of claims 1 to 10 in combination with a pharmaceutically acceptable carrier. 15. Any compound of claims 1 to 10 which is used for the treatment of tumor cells. 16. A compound as claimed in any one of claims 1 to 10 for use in the manufacture of a medicament for the treatment of tumor cells. 17. Any compound of claims 1 to 10 which is used to inhibit farnesyl protein transferase. 18. Any compound as claimed in any one of claims 1 to 10 which is used in the manufacture of a medicament for the treatment of the inhibition of farnesyl protein transferase.